Research We Fund

Development of peptide-drug conjugates for the treatment of Chronic Myelomonocytic Leukaemia (CMML)

We are aiming to bring a new treatment option to patients with chronic myelomonocytic leukemia (CMML) by utilising CCL2-drug conjugates that specifically target and eliminate cancerous cells. Our leading conjugate shows potent and selective efficacy in killing CMML cells. The proposed work will help us understand how this drug works, which patients are most likely to benefit and how it can be combined with current treatments to achieve the greatest patient benefit.

CLL-1 CAR-T cells and trametinib for the treatment of Ras-mutated CMML and JMML

We hypothesize that demonstrating activity of CLL-1 CAR-T (CLL1CART) cell therapy with or without trametinib in pre-clinical models of chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) is the most efficient method to bring cellular therapy to patients with these orphan diseases. In Aim 1, we will determine the in vitro and vivo efficacy of CAR-T cells redirected against CLL-1 using patient-derived xenograft (PDX) models of CMML and JMML. In Aim 2, we will evaluate the role of combining trametinib with CLL1CART cells. Based on our preliminary data, we hypothesize that trametinib will have direct antileukemia activity and will increase the efficacy of CLL1CART by decreasing T-cell exhaustion and augmenting T-cell fitness.

Development of cellular therapy for CMML and the Immune landscape of response and resistance

We will test the efficacy of CAR T cell therapy for CMML. We will modify the tumor microenvironment to enhance their efficacy. and we will upscale CAR T cells to the next level in terms of their genetic structure.

Development of Immunotherapy Targeting U5 snRNP200 for the Treatment of Hematologic Malignancies

The therapeutic landscape of acute myeloid leukemia (AML) has witnessed considerable expansion following recent U.S. FDA endorsements of novel therapies; however, the 5-year survival rate for most adult patients remains below 10%. The absence of immunotherapeutic options for AML can be attributed, in part, to the dearth of identified antigens that selectively discriminate between AML cells and normal hematopoietic precursor cells. Through extensive investigative efforts, our laboratory has made a significant discovery of a membrane antigen, U5 snRNP200, which exhibits promising potential for Fc-engineered anti-U5 snRNP200 therapy. The overarching objective of this endeavor is to engender a novel cellular immunotherapeutic modality with the potential for broad therapeutic impact across a diverse spectrum of myeloid and lymphoid hematologic malignancies.

A phase 1 study of VIPER-101, a CD5-edited dual population chimeric antigen receptor cell therapy, to enhance immunotherapy against T-cell non-Hodgkin lymphoma

In October 2023, LLS made an equity investment in Vittoria to "Support Clinical Development of VIPER-101, a CAR-T Cell Therapy for T-cell lymphomas."

Vittoria Biotherapeutics is developing novel CAR-T cell therapies that transcend the limitations of current cell therapies. Based on technology exclusively licensed from the University of Pennsylvania, Vittoria's proprietary Senza5 platform unlocks the antitumor potential of engineered T cells and utilizes a five-day manufacturing process to maximize stemness, durability, and target cell cytotoxicity. By acting on the fundamental biology of T cells, Senza5 can be used to improve the efficacy of engineered T cell therapies with pipeline applications in oncology and autoimmune diseases.

Vittoria aims to conduct a Phase 1 dose escalation clinical trial for its lead program VIPER-101, an autologous, dual population CD5-knockout CAR-T cell therapy for T-cell Lymphoma featuring the novel Senza5 platform technology. The Phase 1 dose escalation clinical trial is expected to begin soon. Several other products are in earlier preclinical development.

Making an IMPACT on hematology care in Georgia: The Georgia Blood Cancer Trials Network (BCTN)

Winship Cancer Institute is the only NCI-Designated Comprehensive Cancer Center in Georgia, the largest state by land area east of the Mississippi River, and 8th largest state by population. The Winship IMPACT program will leverage existing relationships throughout the state to bring hematology trials to patients in their communities. The goals are to strengthen our relationship with community sites and to increase opportunities for patients to access cutting edge trials throughout our state.

Therapeutic targeting of AML stem cells 2023

The goal of this SCOR project is to identify and eradicate the root cause of acute myeloid leukemia, the so-called leukemia stem cell (LSC). In the previous cycle of this SCOR grant, we developed two unique strategies, each of which efficiently eradicates LSCs in the laboratory. Going forward, we will expand our scientific efforts to further improve these approaches and also conduct clinical trials to determine whether our approaches to killing LSCs will benefit AML patients.

Predicting progression in myeloproliferative neoplasm patients by reconstructing the history of disease in each patient

Blood cancers called myeloproliferative neoplasms occur when one of the blood stem cells picks up a mutation. Some patients stay in the chronic phase of the disease for years whereas others rapidly progress with poor outcome. We recently measured when the cancer mutation first occurs and the rate of expansion of the cancer cells in individual patients. We will develop a method that uses the history of disease in each patient to identify those that are at risk of progression.

Targeting metabolic reprogramming in MDS and AML stem/progenitor cells

Myelodysplastic neoplasms are malignant disorders driven by expansion of diseased hematopoietic stem cells and progression to leukemia. Our investigations have identified the important role of the transporter of amino acid glutamine SLC38A1 in sustaining metabolic demands of rapidly growing malignant stem cells. The goal of this project is to genetically target this transporter to understand its role on tumorigenesis and progression; and to develop SLC38A1 inhibitors as novel therapeutic tools.

Understanding Resistance Mechanism to Enhance CAR-T Immunotherapy for MCL

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by resistance to standard treatments and short survival. For the 2023 LLS MCLII Synergistic Team Award, we have assembled a team of leaders in basic, translational, and clinical research in MCL to tackle the current significant obstacles in understanding and treating MCL. In the last decade, we investigated the therapy resistance mechanism of MCL, and pioneered clinical trials for targeted therapies (ibrutinib, lenalidomide) and chimeric antigen receptor T-cell (CAR-T) therapy. However, despite these dramatic advancements, resistance to these newer therapies, including targeted therapy and CAR-T cells, is seen in over 50% of patients. Thus, it remains an unmet need to better define the mechanisms of resistance and then develop rationally designed strategies to overcome resistance. The overall goal of this Synergistic Team Award is to develop improved curative therapies for patients with MCL at relapse. The goals will be addressed in three highly focused, independent but highly integrated projects that utilize state-of-the-art genomic technologies, patient-derived xenograft models, clinical data and primary MCL samples. With the joint effort of our laboratories, highly interactive and accomplished scientists, and physician researchers from multiple institutions with expertise in MCL and therapy, we are uniquely poised to develop improved next-generation of combination therapy for relapsed MCL patients.

MULTIlayer Predictive models for relapsed MCL after ibrutinib as first line therapY (MULTIPLY)

The MULTIPLY is a large multi-institutional project aimed at characterization of a variety of clinical predictors, both baseline and at relapse through three interconnected Work Packages (WP) with the following objectives: I) Identification of clinical factors affecting prognosis and characterization of relapses; II) Identification of lymph node biomarkers III) characterization of liquid tissue associated biomarkers. All parameters will be integrated through biostatistical and artificial intelligence tools to establish a comprehensive model of relapse prediction and optimal salvage treatment. The proposal is conducted by the Eu-MCL-Network which is the largest group conducting clinical and translational research worldwide in MCL including the largest phase III trials ever conducted. MULTIPLY will exploit the extensive dataset and tissue bank of the TRIANGLE trial that will be presented as abstract #1 at the ASH plenary session. This study will establish a novel standard by the addition of ibrutinib to first-line treatment, but will also raise relevant issues for prediction and management of disease relapse in first-line BTK-era. The expected results will be the generation of comprehensive integrated models for relapse prediction MCL and development of an effective platform to develop rational chemotherapy-free strategies based on genetic alterations of the malignant cell and innovative biomarker-driven strategies.

New Targeted Therapies for Pediatric Acute Myeloid Leukemia

Our research focuses on the preclinical evaluation of new targeted therapies for high-risk subtypes of childhood AML. We are deploying screening approaches to delete each gene, one-by-one, to identify genes whose deletion leads to death of the leukemia cells. We will evaluate drugs developed against these targets in state-of-the-art models of pediatric AML. Our goal is to translate the most promising findings to clinical trials for children with these very poor outcome subsets of AML.

A Multi-Center, Multi-National Investigation of Survivorship and Patient-Reported Symptoms in Erdheim-Chester Disease

Advances in the treatment of Erdheim-Chester Disease (ECD) have led to a growing survivor population; however, there is a lack of information on the burden of chronic health problems, symptomatology, psychological dysfunction, and mortality experienced by this group of individuals. We propose a multi-institutional international study in collaboration with the ECD Global Alliance to answer these critical questions. Results from our study will help in counseling patients in the clinic about what to expect in the future and develop interventions to reduce the risk of health issues and disease or treatment-related symptoms.

Targeting HSP70 to Immune Effector Cells to Overcome the Immune Suppressive Myeloma Microenvironment

Development of a strong anti-cancer immune response requires coordinated action of the innate and adaptive parts of the immune system, but cancer cells alter their environment to suppress virtually every step in this process, which promotes cancer progression and treatment resistance. One promising strategy could be to target Heat shock protein 70 (HSP70), which plays an important role in both innate and adaptive immunity, and we therefore developed a series of novel antibodies to HSP70, one of which cured mice of multiple myeloma. Based on strong preliminary data, we propose additional studies to better understand how this antibody activates various types of immune cells, how it works against both cancer cells and modifies the immune environment in mouse models, and how it could work even better in combination with other agents against myeloma. Since this antibody is already being developed into a drug for phase I clinical trials, these studies will directly inform its use in the clinic against multiple myeloma, and possibly against other blood-related cancers such as B-cell lymphomas.

211Astatine-CD123 Radioimmunotherapy for Cancer (Stem) Cell-Directed Treatment of Acute Leukemia

Because acute leukemias are very sensitive to radiation, radioisotopes are ideal payloads to arm antibodies against these difficult-to-cure, aggressive blood cancers. Here, we will develop fully human anti-CD123 antibodies carrying the highly potent alpha-emitter astatine-211 (211At) as a new therapy for acute leukemia. CD123 is broadly displayed on acute leukemia cells in most patients and overexpressed on leukemic stem cells but is only found on a small subset of normal blood cells, enabling the use of 211At-CD123 radioimmunotherapy in the transplant and non-transplant setting with limited toxicities to normal tissues.

Development of a novel BCL2L1 armored CAR T-cell and a tumor-immune interactome in multiple myeloma

Novel immune approaches have revolutionized the treatment paradigms in multiple myeloma (MM) with deep responses seen in heavily pretreated patients. However responses are largely not durable with significant gaps remaining in our understanding of the mechanisms mediating the immune escape to to CAR T cells and T cell engagers. Harnessing the power of single cell immunogenomics and building on the knowledge we amassed to date, we plan to address these therapeutics and mechanistic challenges firstly through the informed design and clinical development of a BCL2L1 armoured BCMA-targeting CAR T cell, and secondly by establishing a dictionary of the MM-TME interactome through serial interrogation of primary MM cells and their immunome generating a dynamic risk prediction model to better guide the delivery of immuno-therapeutics.

A phase 1b/2 study targeting apoptotic and signaling pathways in T-acute lymphoblastic leukemia

T-acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia with limited treatment options after first-line chemotherapy. Our preclinical work in animal models of T-ALL demonstrated the activity of a novel-novel combination treatment strategy, which includes LP-118 (activator of suicide pathways within leukemic cells) and tyrosine kinase inhibitors (inhibiting growth-promoting LCK and ACK1 signaling pathways). Leveraging the mechanistic insights gained from our laboratory work, we propose a phase Ib/II study investigating the feasibility and efficacy of the combined LP-118, ponatinib, and salvage chemotherapy in patients with relapsed T-ALL. This precision medicine approach addresses an unmet need in a fatal disease which lacks effective therapies.

Strategic combinations to overcome therapeutic resistance and relapse in acute myeloid leukemia

Acute myeloid leukemia (AML) is the most fatal type of leukemia and has a high rate of relapse following current therapies. We have recently uncovered that RSPO3-LGR4 pathway is a key regulator of leukemia-initiating cell activity and is exclusively activated in relapsed and refractory AML. Our project aims to investigate the mechanistic link between the pathway activation and therapy resistance, and design combination therapies that would overcome resistance and improve the treatment of relapsed leukemia.

Targeting GCK as a novel and selective therapeutic strategy against RAS mutated Multiple Myeloma

RAS/MAPK mutations are the key drivers in MM, which occurs in 50% of newly diagnosed and higher in relapsed MM patients. However, RAS remains undruggable in MM. We found that RAS mutation MM growth is highly dependent on germinal center kinase(GCK). The goal of this project is to develop small molecule inhibitors against GCK with the expected outcome to provide novel treatments for relapsed/refractory and especially multi-drug resistant MM with RAS mutation, as well as other B-cell malignancies.

CD70-directed CAR T-cell therapy for the treatment of relapsed/refractory pediatric AML

In this project, we will test an innovative therapy called CAR T-cell therapy for children with a type of cancer called AML. In the laboratory, we have identified and developed a powerful CAR T-cell therapy that targets a protein called CD70 on AML cells. We propose to now develop a clinical trial in which we will study the effects of this CD70.CAR T-cell therapy in children with AML.

Development of mutant GTPase-specific degraders for peripheral T cell lymphoma treatment

This project aims to develop targeted therapies against peripheral T cell lymphoma (PTCL), a diverse group of aggressive blood cancers with poor clinical outcomes. This project is tightly relevant to cancer control and treatment, promising to advance our understanding on how blood cancers initiate and progress, and lead to new therapeutics for the treatment of peripheral T cell lymphoma (PTCL). We will develop targeted therapeutics to engage an oncogenic RHOA GTPase mutant to treat PTCL and other types of tumors with similar genetic backgrounds.

Targeting acetyl-CoA synthetase 2 to remodel obesity-evoked inflammatory microenvironment in myeloma

Our proposal aims to develop a novel strategy to improve therapeutic efficacy for patients with multiple myeloma by remodeling obesity-induced inflammatory microenvironment. We hypothesize that acetyl-CoA synthetase 2, which is stimulated by obesity, enhances inflammatory cytokine production from myeloma cells, leading to an inflammatory niche where anti-tumor function of CD8+ T cells is dampened, and tumor growth is promoted. Our study will be the first to explore a novel insight for how obesity impacts the interaction between myeloma cells and microenvironment. In preparation of using the inhibitor of acetyl-CoA synthetase 2 in the clinical setting, we will establish its potential as a single agent or in combination of other chemo- or immuno- drugs to treat myeloma.

Memory-like natural killer cells and venetoclax to eradicate measurable residual disease in AML

This proposal is to conduct a phase I (early phase) clinical trial to test whether the combination of the approved targeted therapy venetoclax with memory-like Natural Killer (NK) cells is safe and active in patients with acute myeloid leukemia (AML). Based on laboratory research at Dana-Farber Cancer Institute, we believe that the addition of memory-like NK cells obtained from an haploidentical (‘half matched’) donor will be able to eradicate residual leukemia cells left over after prior venetoclax treatment and hence prevent a future relapse of the disease. A total of 10 patients will be treated with two different doses of NK cells and a constant dose of venetoclax. We also plan scientific studies on patient samples to learn more about the function of NK cells when combined with venetoclax, evaluate for clearance of residual leukemia cells with this combination therapy and explore potential resistance mechanisms.

Health Insurance and End-of-Life Care for People with Hematologic Malignancies

Patients with blood cancers from racial and ethnic minority groups are more likely to experience suboptimal end-of-life (EOL) care. These disparities may be partially driven by health insurance differences but there is limited research examining insurance access as a potential contributor to EOL care disparities for this population. We will leverage complementary local and national datasets to assess the relationship between insurance status and type with EOL quality measures. We will also develop a Blood Cancer Health Insurance Initiative to translate our research findings to policy initiatives to dismantle disparities in access to high-quality EOL care for patients with blood cancers. We will translate our research findings to policy initiatives to dismantle disparities in access to high-quality EOL care for patients with blood cancers.

Investigating the Impact of Insurance Coverage on Access to Care and Outcomes among Lymphoma Patients

In this proposal we will investigate the association between insurance coverage and access to care, survival, and financial hardship among patients across Non-Hodgkin lymphoma (NHL) subtypes and to what extent insurance coverage explains and modifies racial disparity in access to care and outcomes. To this end, we will use the Optum Clinformatics DataMart database, the Texas Cancer Registry, the Harris Health System Cancer Database and Data from the Lymphoma Epidemiology of Outcomes (LEO) Cohort Study. These four databases will provide a sample that covers a diverse patient population in terms of insurance coverage, race and ethnicity, and geographic regions. The LEO Cohort Study also provides information on self-reported financial toxicity that is not available in cancer registries, administrative claims data, or surveys. This study will reveal whether insurance coverage, neighborhood socioeconomic factors and healthcare resources are associated with access to care and outcomes of NHL patients.

The Impossible Choice: The Role of Insurance Design on Financial Toxicity and Access to Care for Individuals with Blood Cancer

The overall goal of this project is to understand the role of insurance design on financial toxicity and access to care among individuals with blood cancer. To understand this interplay, we will use a unique and innovative linkage of the 2012-2019 Colorado Cancer Registry (CCR) to the 2013-2021 Colorado All-Payer Claims Database and the LexisNexis and TranUnion financial and life event databases. Our specific aims are to 1) Estimate the number of individuals with blood cancer who are potentially underinsured over time relative to individuals with solid tumors or no history of cancer; 2) Examine the relationship between being underinsured and experiencing financial toxicity after diagnosis in individuals diagnosed with blood cancer relative to those with solid tumors or no history of cancer; and 3) Examine differences in access to cancer care including time to treatment, treatment intensity and survival in underinsured individuals with blood cancer versus those with more generous insurance coverage.

Targeting mutated MYD88 pro-survival signaling in B-cell malignancies

Our laboratory and those of others discovered highly recurring mutations in the gene MYD88 which are found in patients with various B-cell cancers including Waldenstrom’s Macroglobulinemia (95-97%), ABC Subtype of Diffuse B-cell Lymphoma (30-40%), Primary Central Nervous Lymphoma (80%), Marginal Zone Lymphoma (10%) and Chronic Lymphocytic Leukemia (5-10%). Our laboratory and those of others showed that mutated MYD88 triggers BTK, which is the target of BTK-inhibitors like ibrutinib, acalabrutinib and zanubrutinib though complete remissions are rare with these agents largely in part because other pro-survival molecules are activated by mutated MYD88 such as HCK and IRAK1. In these studies, we will develop potent and selective inhibitors to HCK and IRAK1, including PROTACs which inhibit and degrade these molecules, using lead molecules and scaffolds whose target selectivity and activity we previously validated. We will also investigate the mechanisms underlying the inactivation of the Inhibitor of BTK (IBTK) as a potential new target for development of inhibitors for use in MYD88 mutated lymphomas.

Autologous CD22 CAR T cell Therapy for the Treatment of non-Hodgkin Lymphoma

CD19 targeting chimeric antigen receptor (CAR) T cell therapies (CAR19) are effective treatments for patients with non-Hodgkin Lymphoma (NHL), however, the majority of these patients will relapse. We have now evaluated a CD22 targeting CAR T cell therapy (CAR22) in patients who have large B cell lymphoma who have relapsed after CAR19 therapy and found that this therapy is both safe and effective resulting in a high rate of durable complete responses. We will now test this promising CAR22 for the first time in patients with other non-Hodgkin Lymphoma subtypes including mantle cell lymphoma, follicular lymphoma, and other CD22-expressing lymphomas.

Towards clinical testing of epitope editing to enable novel adoptive immunotherapies

Innovations in gene engineering have made it possible to reprogram immune cells to attack specific targets on cancer cells, allowing the first adoptive cellular immunotherapies, known as CAR T cells, to be approved by the FDA for the treatment B lymphoblastic leukemia. A similar approach is currently under development for AML, but in contrast to B-ALL, there is no leukemia-specific target which would be amenable to targeting by immune cells without incurring severe adverse effects. Here, we aim to modify normal bone marrow stem cells used for allogeneic transplantation to make them resistant to CAR-T cells, thus enabling targeting proteins essential for tumor survival without the risk of severe toxicity on the healthy tissue counterpart.

Elucidating the role of FAM72A in EBV-driven B cell lymphomagenesis

This work focuses on characterizing the role of FAM72A in EBV-driven B cell tumorigenesis. This protein is upregulated by EBV during the transformation of B cells and overexpressed in many hematologic cancers. Using a combination of in vitro and in vivo EBV transformation models, high-throughput drug screens, and structural analysis we aim to find small molecules inhibitors that target FAM72A and determine if these drugs can prevent or hinder EBV-associated B cell malignancies.

Characterization and Targeting of Tumor-Associated Monocytes/ Macrophages that Limit the Efficacy of PD-1 Blockade in Lymphoma

Inhibition of the PD-1 exhaustion pathway enables the immune system to attack cancers. PD-1 blockade is now a standard treatment for relapsed classic Hodgkin Lymphoma (cHL) and a component of experimental frontline therapy. In patients with cHL, a newly identified population of monocytes/macrophages limits the efficacy of PD-1 blockade. We will characterize and target these tumor-programmed monocytes/macrophages for therapeutic benefit in patients with cHL and other lymphoid malignancies.

Bone Marrow Stromal Cell Senescence Induced by Dnmt3a-Mutant Hematopoiesis Drives Clonal Hematopoiesis and Transformation to Myeloid Malignancy

This project focuses on how age-associated clonal hematopoiesis (CH) alters the bone marrow (BM) microenvironment, and whether this promotes transformation of CH to acute myeloid leukemia (AML). I will utilize single cell RNA-seq data, genetic knockout models, and targeted inhibitors to perturb the non-hematopoietic and hematopoietic compartments of a mouse model of CH. The goal is to determine if manipulation of the BM microenvironment can attenuate CH and prevent AML transformation.

Identifying novel regulators of leukemic progression in GATA2-deficiency syndrome

GATA2 deficiency is an inherited pediatric syndrome with a high rate of progression to myeloid malignancy, the mechanisms of which remain largely undefined. Here, we will use our recently generated mouse model, Gata2R396Q, to determine the effects of GATA2 deficiency on hematopoietic function and identify novel drivers of myeloid malignancy via focused CRISPR screens. Our work will provide further insight into the mechanisms driving leukemic progression of this syndrome.

An integrated liquid biopsy framework for surveillance of residual disease and host immune status of T-cell lymphomas

I aim to develop an accurate disease monitoring system and identify immunologic determinants of development and progression in T-cell lymphoma (TCL). I will integrate noninvasive liquid biopsy methods by high-throughput sequencing. I will study blood samples at various milestones, including pre-diagnostic, diagnostic/baseline, and post-treatment specimens during the natural history of TCL. Using these novel tools and unique specimens, my goal is the development of effective therapies for TCL.

Deciphering the role of p53 signaling in NPM1-mutant AML

NPM1c and TP53 mutations are exclusive in acute myeloid leukemia (AML) despite both being commonly present in patients, suggesting a fitness disadvantage for cells with co-occurring mutations. However, the mechanisms underlying this exclusivity have not been explored. This project will utilize novel models to dissect the importance of TP53 signaling in NPM1c+ (pre)-leukemic stem cells. Generated results may highlight therapeutic opportunities for improved risk management of NPM1c+ AML patients.

Exploring the roles of EZH2 mutation for the development of double hit lymphoma and acquisition of chemotherapy resistance

We aim to clarify the role of EZH2 mutations in the development of double hit lymphoma (DHL) and acquisition of chemo-resistance. We confirmed that Ezh2 mutation is essential to develop aggressive murine GCB lymphoma and deplete T cells from tumor in combination with BCL2 and MYC. The mice showed resistance to chemotherapy and the combination with EZH2 inhibitors improve the outcome in vivo. Our goal is to show the synergy and propose a new mechanism-based therapeutic approach for DHL.

Development of novel BTK-MALT1 dual inhibitors to treat MCL

Most patients respond well to drugs that inhibit an important MCL target named BTK. However, almost all of them will eventually relapse and then do very poorly. Inhibition of MALT1, a target which is biochemically downstream of BTK, may rescue many of these patients, and inhibiting both BTK and MALT1 may be better still. Developing a drug that inhibits both targets at the same time, from the beginning of treatment, will avoid some complications and likely be best of all; we will find out.

Epigenetic Mechanisms in Acute Myeloid Leukemia

The goal of this project is to investigate the role of the epigenetic regulator Eleven-Nineteen-Leukemia (ENL) and its cancer mutations in acute myeloid leukemia (AML). Our studies leverage the expertise in chromatin biology, functional genomics, and AML modeling, as well as unique chemical compounds and mouse models. Results from this project will provide novel biological insights into our understanding of AML pathogenesis and facilitate the development of novel epigenetic therapies.

Modeling and targeting leukemic transformation of human hematopoietic stem cells

Our research seeks to understand how ordered acquisition of oncogenic mutations transforms human hematopoietic stem cells into myeloid malignancies. We leverage patient-derived induced pluripotent stem cells and primary normal and malignant stem cells to study how mutation cooperation drives leukemic progression in vitro and in vivo. Our long-term goal is to identify disease mechanisms and develop targeted therapies to eradicate malignant stem cells.

Improving CAR T-cell Therapy Efficacy in Acute Lymphoblastic Leukemia by Optimizing Design and Placement

Pediatric acute lymphoblastic leukemia (ALL) that is resistant to standard therapy is a challenge that has been partially overcome by T-cell therapy, yet relapse still occurs in up to 50%. We are conducting two clinical trials that test a next-generation T-cell therapy and the first incorporation of T-cell therapy into initial therapy. These trials will inform future development and the optimal place for this therapy with the goal of improving cure rates for children with very high risk ALL.

Clinical and molecular determinants of CLL eradication with targeted combination therapy

The genomic architecture of residual CLL and molecular determinants of disease progression after targeted combination therapy are unknown. In a phase 2 study of zanubrutinib and venetoclax in CLL, I will investigate the depth of response and genomic changes using cellular and circulating tumor DNA. Data generated from this proposal will provide foundational evidence to develop genomic markers for non-invasive monitoring of treatment response and precise prediction of outcome.

Supporting development of RNA-targeting molecules for blood cancers

In June 2023, LLS made an equity investment in Rgenta Therapeutics to "Support development of RNA-targeting molecules for blood cancers." 

Rgenta Therapeutics is developing a pipeline of oral, small-molecule RNA-targeting medicines with an initial focus on oncology and neurological disorders. Rgenta has a proprietary platform to mine the massive genomics data to identify targetable RNA processing events and to design small-molecule glues to modulate the interactions among the spliceosome, regulatory proteins, and RNAs. 

Rgenta is working closely with LLS TAP to further develop RNA-targeting molecules by supporting preclinical studies with the goal of moving towards clinical development in hematological malignancies. 

A phase 1/2 study of BI-1206, a monoclonal antibody to CD32b (FcyRIIB), in combination with rituximab in patients with indolent NHL that has relapsed or is refractory to rituximab

In January 2023, LLS made an equity investment in BioInvent to "Support Clinical Development of BI-1206 for NHL Indications and BI-1808 for T-Cell Lymphoma Indications Including CTCL."

BioInvent International AB is a clinical-stage biotech company that discovers and develops novel and first-in-class immuno-modulatory antibodies for cancer therapy, with currently four drug candidates in five ongoing clinical programs in Phase 1/2 trials for the treatment of hematological cancer and solid tumors, respectively. The Company's validated, proprietary F.I.R.S.T™ technology platform identifies both targets and the antibodies that bind to them, generating many promising new drug candidates to fuel the Company's own clinical development pipeline and providing licensing and partnering opportunities.

BI-1206 is a novel anti-FcyRIIB antibody currently being studied in two Phase 1/2 trials, in combination with rituximab in NHL (NCT03571568) and in combination with pembrolizumab in solid tumors (NCT04219254).

A phase 1 study of DR-01, an anti-CD94 monoclonal antibody, in patients with large granular lymphocytic leukemia or cytotoxic lymphomas

In November 2022, LLS made an equity investment in Dren Bio to "Support Clinical Development of the DR-01 Program for Rare Leukemia & Lymphoma Indications Including Large Granular Lymphocyte Leukemia (LGLL) and Cytotoxic Lymphomas."

Dren Bio is a clinical-stage biopharmaceutical company focused on developing therapeutic antibodies for the treatment of cancer, autoimmune and other serious diseases. Dren Bio’s pipeline encompasses two distinct programs, the first focusing on the engineering of antibodies with enhanced antibody-dependent cellular cytotoxicity (ADCC) capabilities and the second revolving around its proprietary Targeted Myeloid Engager and Phagocytosis Platform.

DR-01 is a novel antibody targeting CD94 which is known to be upregulated on LGLL cells. DR-01 functions through depletion of target cells via ADCC by means of fratricide, a method in which the same cell type induces ADCC on each other. A Phase 1 trial has been initiated to assess the safety and efficacy of DR-01 in previously treated LGLL patients (NCT05475925).

Understanding and Overcoming Mechanisms of Immune Evasion after Allogeneic Transplant

Outcomes for patients with acute myelogenous leukemia who relapse after transplantation are dismal. This SCOR brings together an international group of collaborators with deep expertise in genomics, epigenetics, antigen presentation, and immune-regulation. They will focus on mechanisms of immune evasion by leukemia cells, identifying effective T cell responses to those evasive processes, and providing critical insights into the optimal approaches to model new and promising targets for immunotherapy with a goal of eliminating leukemia recurrence.

Research Infrastructure to Promote Enrollment of Underserved Patients on Clinical Trials

The goal of the Clinical Trial Network of South Texas is to expand access to high quality clinical trials for under-represented minority (African American and Hispanic) patients with lymphoid cancers who receives care at the UT San Antonio Mays Cancer Center (MCC) and community oncology centers in South Texas. To achieve this goal, we will leverage the existing partnership between MD Anderson Cancer Center (MDACC) and its robust clinical trial infrastructure to identify and deploy suitable clinical trials. We also will strengthen the research infrastructure at MCC and community sites, including providing equipment, clinical trial navigation support, and oversight to successfully deploy trials. By establishing MDACC/MCC as a hub for clinical trials, developing the necessary research infrastructure at community oncology centers, and allowing patients to participate in clinical trials at their local oncology centers, this IMPACT program has the potential to improve clinical outcomes.

GNAS as a new therapeutic target for MDS

Myelodysplastic syndrome (MDS) is a blood disease with poor prognosis and frequent progression to acute myeloid leukemia (AML). There are currently no effective treatments. This proposal is based on a recent discovery by my group and proposes to investigate a protein called G⍺s (alpha subunit of the stimulatory G protein), as a novel therapeutic target for MDS. If successful, this work can lead to novel therapies that can transform the treatment of MDS, AML and possibly other cancers.

Discovering the function and targeting dysregulated nuclear condensates in myeloid leukemia

Although molecular targeted therapy has dramatically changed how we treat cancer, the treatment for acute myeloid leukemia (AML) remains focused on the use of cytotoxic drugs with many patients eventually relapsing with their disease. Our studies have a uncovered a new nuclear structure that is dysregulated in myeloid leukemia. This proposal studies the identity and function of this nuclear body in human AML and strives to identify novel therapeutic strategies and targets in leukemia.

Establishing Hematology Clinical Trial Hubs within the City of Hope Community and Affiliate Network

City of Hope (COH) has embarked on a strategic initiative to optimize our clinical network and increase research capacity at our Community and Affiliate Network (CAN) sites in Southern California. I would like to spearhead this endeavor for the Hematology program at our new Irvine campus in Orange county, which is set to open in August 2022. We are employing a hub-and-spokes model, in which the Duarte main campus is the main research center, with 3-5 multi-disciplinary CAN sites ultimately designated as research hubs. These CAN sites (hubs) will serve geographically proximal practice sites (spokes), which will refer patients for treatment on clinical trials at either the CAN site itself or at the main Duarte campus. Following a 6-month pilot for optimizing staffing, investigational pharmacy setup, specimen and data collection in Irvine, an additional CAN site will be initiated each year over a 5-year period to allow a wider area of Southern California residents to have access to high quality and impactful clinical trials in Hematology. Our ultimate goal is to accrue 20-50 patients per year from the community, depending on the number of sites activated each year.

Interrogation of glutathione biology in relapsed acute myeloid leukemia stem cells

Acute myeloid leukemia (AML) is a devastating blood cancer. Most AML patients will initially respond to standard therapy; however, for many patients the disease recurs resulting in patient death. Consequently, there is an urgent need to develop new therapeutic strategies for relapsed AML patients. The objective of our proposal is to understand and target properties specific to relapsed AML cells with the overall goal of improving relapsed AML patient outcomes.

Impact of Health Insurance on Mortality for Children and AYAs Newly Diagnosed with a Blood Cancer: A Population-Based Multistate Evaluation

Lacking continuous insurance is a key barrier to access to timely care. This study will provide the first evidence of whether insurance continuity provides a survival benefit, and how Medicaid expansion under the Affordable Care Act affects insurance continuity and the associated downstream changes in survival for children, adolescents, and young adults with blood cancers. This study will inform policy interventions toward increasing access and reducing disparities in blood cancer outcomes.

Making the Right Choice: Medicare Plan Selection and Access to Cancer Care

Selecting a Medicare plan is a time-sensitive and complex decision with substantial financial implications, particularly for individuals with cancer. The proposed project evaluates the financial and health outcomes for individuals selecting different Medicare coverage options and how these outcomes vary by the presence and timing of a cancer diagnosis. The goal of this work is to identify opportunities to improve plan selection and reduce inequities in cancer care and outcomes.

Targeting aberrant non-canonical NF-κB pathway activation in B-cell lymphomas

The impact of biological heterogeneity on treatment outcomes is evidenced by a large proportion of lymphoma patients who experience relapsed/refractory disease. To address this knowledge gap, we sequenced primary lymphoma samples and found recurrent mutations in the non-canonical NF-kB pathway (NC NF-kB) and uncovered the NIK kinase as a targetable candidate. Our next steps focus on using advanced genetic modelling approaches to provide preclinical rationale for targeting NC NF-kB in lymphomas.

TCR directed immunotoxins and antibody drug conjugates for the treatment of T cell malignancies

Few treatment options are available for T cell leukemias and lymphomas, collectively called T cell cancers that affect ~100,000 patients worldwide each year. The current proposal will generate new antibodies attached to drugs and toxins that kill the T cell cancers. Importantly, the antibodies will preserve enough healthy T cells to maintain a functioning immune system. These modified antibodies may improve patient outcome and limit side effects associated with traditional chemotherapies.

Overcoming RAS-driven Mechanisms of Resistance in Leukemia

The mitogen-activated protein kinase (MAPK) pathway is activated in high-risk leukemia and is a hallmark of resistance to therapies. This project uses patient-derived xenograft models of relapsed pediatric ALL and AML with activated RAS/MAPK to test whether clinically relevant MAPK mutations activate the VAV3/RAC pathway and if pharmacological inhibition of that pathway by a small molecule we developed synergizes with a MAPK-inhibitor to provide a new treatment strategy for RAS-driven leukemia.

A Phase I/II Study of the Combination of ALX148, Rituximab and Lenalidomide in Patients with Indolent and Aggressive B-cell Non-Hodgkin Lymphoma

SIRPα+ macrophages mediate resistance to lenalidomide in B-cell lymphoma, limiting the activity of immunotherapy for these patients. Therefore, we propose a phase I/II study, investigating the safety and efficacy of ALX148, a novel fusion protein of the SIRPα binding domain, in combination with rituximab and lenalidomide in patients with B-cell lymphoma. We hypothesize that this combination will be safe and effective, providing a chemotherapy-free option for these patients.

Therapeutic exploitation of novel mouse models and metabolic interventions in leukemia

Our research program aims to gain a deeper understanding of the pathobiology of T-ALL and HSTL.

To this end, we will use novel mouse models, cutting-edge techniques and comprehensive genetic, pharmacological and metabolic interventions. In addition, we will perform unbiased experiments to identify novel therapeutic targets.

Our goal is to uncover new tools and targets for the treatment of T-ALL and HSTL, which could be used for the benefit of patients in the short/mid-term.

Analysis and therapeutic targeting of the immune regulatory and ubiquitination pathways in Anaplastic Large Cell Lymphoma and Hodgkin Lymphoma

My lab is focused on the immune regulatory mechanisms and ubiquitin-dependent machinery in lymphoma. We have established multiple high-throughput screening technologies and animal models to rapidly and accurately identify critical pathways that are suitable for targeted therapy and immunotherapy. Gaining insight into the pathological roles of these pathways can lead to improved understandings of the molecular circuitry that drives lymphoma pathogenesis and provide novel therapeutic strategies.

Genetic pathways of myeloid transformation and treatment response

Our central goal is to improve clinical outcomes in patients with myeloid malignancies through developing an enhanced mechanistic understanding of disease. We use multiomic analyses of primary patient samples combined with complementary laboratory models using mice and cell lines to generate and test our hypotheses. The results of our studies will help improve patient outcomes by identifying strategies to mitigate risk of disease progression/relapse and treatment toxicity.

Understanding the clonal origin, evolution, and progression of myeloid malignancies

The overarching focus of my research is to understand the clonal origin, evolution, and progression of myeloid malignancies and biological and clinical factors that influence the process. We tackle this question by analyzing patient samples with integrated approach combining single-cell omics, evolutionary genetics, and computational analytics. The ultimate goal of our research is to develop clinical strategies for early detection, prevention, and treatments of myeloid malignancies.

Stratified treatment of newly diagnosed MCL based on the presence or absence of high risk features utilizing non-cytotoxic agents.

We believe that regimens without chemotherapy can induce significant and durable remissions in patients with Mantle cell lymphoma (MCL). We will confirm this hypothesis by conducting two clinical trials stratified by the presence or absence of high risk features. We will utilize BH3 profiling and MRD testing to assist with predicting treatment response and remission. Our goal is to verify the efficacy of our regimen and prove the utility of BH3 profiling and MRD testing in outcome prediction.

Improving Bispecific CD20/CD19 CAR T-cell Therapy to Overcome Resistance Mechanisms in B-cell Malignancies

The objective of this proposal is to improve bispecific anti-CD20/anti-CD19 CAR T-cell activity and persistence by understanding impact of cell manufacturing parameters on final engineered CAR-T product and determining resistance mechanisms in relapsing patients. We will analyze patient apheresis, final CAR-T product, and peripheral blood samples from subjects enrolled on an ongoing clinical trial (NCT04186520). Data from these studies will advance CAR T-cell therapies for lymphoma patients.

Early Detection and Intervention in Smoldering Multiple Myeloma: population-based screening and treatment; Edit-SMM

We build on the success from the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study, where over 80,000 consented to a nationwide screening for MM precursors. A unique cohort of patients with SMM diagnosed in iStopMM will be followed by clinical evaluation, linking to central health data registries, using novel biomarkers, and in-depth genetics. With precision early treatment we aim to induce a paradigm shift leading to improved quality of life and potentially a cure for MM.

Defining the Biologic and Therapeutic Significance of the Novel Long Noncoding RNA MYND in Multiple Myeloma

Long non-protein coding RNAs (lncRNAs) are fundamental for proper cell function, but their purpose is poorly understood in multiple myeloma. To systematically identify myeloma-promoting lncRNAs, we integrated gene expression profiling of myeloma patients with high-throughput loss-of-function studies in cell lines. Moreover, we optimized strategies to antagonize myeloma-promoting lncRNAs, thus paving the way to developing lncRNA inhibitors as the next generation of therapy.

Mechanisms of Pathogenesis by MYB Fusions in Blastic Plasmacytoid Dendritic Cell Neoplasm

The transcription factor MYB has long been associated with leukemia, but how it contributes to disease is poorly understood. Fusions of MYB to other proteins, causing MYB activation, are found in patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN), but rare in other leukemias. I am using recently developed techniques to gain insight into how MYB fusions cause BPDCN. This will enable both new treatments for BPDCN and better understanding of the role of MYB in other leukemias.

Investigating the Role of ASXL1 Mutations in CALR-mutated Myeloproliferative Neoplasms

My research focuses on myeloproliferative neoplasms (MPN) and the mutations that drive the progression of these blood cancers. Currently, I am investigating mutations in the gene ASXL1, which are associated with a poor prognosis. I am using mouse models and patient-derived cells to determine how ASXL1 mutations mediate epigenetic changes in MPN. My goal is to identify ways of targeting the pathological mechanisms caused by ASXL1 mutation, resulting in new treatment strategies for patients.

Precision Medicine For DNMT3A-Mutant T-cell ALL

T-cell ALL is an aggressive blood cancer with poor overall survival, high relapse rates, and significant treatment-related side effects. Using primary T-ALL patient samples, this project will study the importance of JAK/STAT signaling and the gene BIRC5 in the pathology of T-ALL driven by DNMT3A mutations using genetic and pharmacological tools. The goal of this proposal is to develop precision medicine approaches for DNMT3A-mutant adult T-ALL patients, a group with poor clinical outcomes

Precision Targeting of Hairy Cell Leukemia using Chimeric Antigen Receptor T cells

Though effective treatments in hairy cell leukemia and variant (HCLv) exist, they are associated with profound immunosuppression; thus, more targeted, non-toxic therapies are warranted. In order to specifically target leukemic cells while sparing most normal B cells, we will develop a novel chimeric antigen receptor T cell immunotherapy against the IGHV-4-34 B-cell receptor that is found in a significant subset of HCL and associates with poor prognosis.

Detection and treatment of Adult T cell leukemia/lymphoma in the premalignant stage.

Clonally expanded T cells carrying somatic mutations circulate in the premalignant phase of Adult T cell leukemia/lymphoma (ATL). We will develop capture-sequencing of recurrent ATL-driver mutations for use as a diagnostic tool for the detection/characterization of ATL-like clones in individuals with high risk of ATL, and, in an aligned clinical study, we will test whether a novel monoclonal antibody (targeting C-C chemokine receptor 4) can eradicate these high-risk cells.

A First-in-human Clinical Trial of CD5 knocked-out Chimeric Antigen T Cells for T-cell Lymphomas

This proposal seeks to develop for the first time in humans a novel CD5 knocked out (KO) anti-CD5 chimeric antigen receptor T cell (CART) product for patients with relapsed or refractory T-cell lymphomas. In Aim#1, we will generate and test a clinical-grade CD5 KO CART5 product, and in Aim#2, we will perform a phase I clinical trial. This project is highly relevant to those parts of the LLS's mission that pertain to the development of personalized and novel therapies for cancer treatment.

Therapeutic targeting of T-cell acute lymphoblastic leukemia using an AKR1C3-activated prodrug

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy that is exceptionally difficult to cure after relapse. We have previously shown that T-ALL expresses high levels of the enzyme AKR1C3, leading to clinical trials of AKR1C3-activated prodrugs. This project will focus on identifying the determinants of responses to AKR1C3-activated prodrugs in T-ALL and optimizing the use of a second generation AKR1C3-activated prodrug, SN36008, in T-ALL patient-derived xenografts.

Improving CAR-T cell therapy outcomes for patients with for aggressive lymphoma and multiple myeloma

Despite the promise of CAR-T cell immunotherapy for patients with lymphoma and multiple myeloma, a significant proportion of patients fail to respond or relapse following treatment. This project will focus on the clinical translation of a new treatment designed to improve durable response rates by combining CAR-T cell therapy with a new class of anticancer drugs called SMAC-mimetics. The results will provide the evidence base to drive a first-in-human clinical trial of this combination strategy.

Prediction and prevention of therapy-related myeloid neoplasms following autologous transplantation

The proposed studies will identify alterations in hematopoietic regulation that predict for risk for therapy-related myeloid neoplasm (TMN) and improve understanding of disease evolution to guide strategies to prevent TMN in patients receiving autologous hematopoietic cell transplantation (aHCT) for lymphoma. They will investigate alterations in hematopoietic function in peripheral blood stem cell used for aHCT, and serial evolution of hematopoietic defects leading to development of TMN.

Targeting the MMP-13/PD-1H signaling axis for multiple myeloma bone disease and immunosuppression

Multiple myeloma is an incurable blood cancer complicated by bone diseases and compromised immune system. Our work indicated that checkpoint inhibitor PD-1H(VISTA) functions as the MMP-13 receptor, and the MMP-13/PD-1H signaling axis plays a critical role in multiple myeloma induced bone disease and immunosuppression. Therefore, immunotherapy targeting the novel MMP-13/PD-1H interaction module represents a novel approach to cure this devastating cancer.

Targeted combination therapies for leukemia with NUP98 translocations

Leukemia patients with chromosomal translocations of the Nucleoporin (NUP98) gene suffer from very poor prognosis. In this project we will identify new treatment for these patients by combining menin inhibitor with FDA approved drugs. We will evaluate effectiveness, mechanism of action and biomarkers of treatment response to these combinations in advanced pre-clinical models of NUP98 leukemia. We expect these studies will lead to future clinical trials in AML patients with NUP98 translocations.

Investigating anti-neoplastic effects of beta blockers in multiple myeloma

Multiple myeloma (MM) relies on the bone marrow (BM) niche to progress to refractory disease. We found that beta blockers alter BM niche elements fostering MM growth and also reduce MM cell survival. Our objective is to elucidate the cellular and metabolic basis of how beta adrenergic signals impact the BM niche and MM progression. Knowledge of the prophylactic and therapeutic utility of beta blockers in MM will unravel new means to target neural niche remodeling fueling this fatal malignancy.

Studies on clonal hematopoiesis in the 911 WTC first responders

The terrorist attacks on the World Trade Center (WTC) created an unprecedented environmental exposure to WTC aerosolized dust and gases that contained known and suspected carcinogens including polycyclic aromatic hydrocarbons, polychlorinated biphenyls, polychlorinated furans, dioxins and asbestos. Studies from Dr. Verma's group and others have reported an excess of cancer cases in the WTC-exposed Fire Department of the City of New York (FDNY) firefighters, including a trend towards higher incidence of multiple myeloma and leukemias. He now will be deep sequencing a large group of WTC-exposed firefighters to look for clonal hematopoiesis (CH) which is an acquisition of leukemia associated mutations associated with increases in the risk of hematologic cancer.

A phase 2 study of Bexmarilimab, an anti-Clever1 monoclonal antibody, in combination with azacitidine in patients with high-risk MDS

In June 2022, LLS made an equity investment in Faron Pharmaceuticals to "Support Clinical Development of the Bexmarilimab Program for Leukemia Indications."

Faron is a clinical stage biopharmaceutical company developing novel treatments for medical conditions with significant unmet needs caused by dysfunction of our immune system. The Company currently has a pipeline based on the receptors involved in regulation of immune response in oncology, organ damage and bone marrow regeneration. 

Bexmarilimab, a novel anti-Clever-1 humanized antibody, is its investigative precision immunotherapy with the potential to provide permanent immune stimulation for difficult-to-treat cancers through targeting myeloid function. A Phase 2 study (BEXMAB) of bexmarilimab in combination with azacitidine is currently enrolling high-risk MDS patients in the US and Finland (NCT05428969).

Merging immune and molecular signals in HCL for improved prognosis and treatment decision making

Our research consortium of diagnostic, translational and clinical researchers will undertake an integrated and novel exploration of the immune and genomic landscape in hairy cell leukemia (HCL) and correlate those data with response to both conventional and newly emerging therapies. We will apply our innovative platforms of digital spatial profiling, whole genome sequencing and circulating tumor DNA to provide highly novel data from our already collected sample bank from over 60 patients with HCL.

Mosunetuzumab with lenalidomide augmentation as first-line therapy for patients with follicular and marginal zone lymphoma

Dr. Olszewski’s trial will examine mosunetuzumab as a first-line treatment for follicular and marginal zone lymphomas—slow-growing types of B-cell lymphoma which remain incurable using current therapies. Mosunetuzumab is a “bispecific antibody” that can trigger an immune attack of patients’ own cancer-killing T-cells against the lymphoma. Dr. Olszewski team will look for characteristics that predict complete responses when this novel immunotherapy is applied as first-line treatment.

Improving the outcomes of young Black adults diagnosed with acute myeloid leukemia

Young Black patients diagnosed with acute myeloid leukemia (AML) have significantly shorter survival compared to White patients. To comprehensively assess genetic, genomic and biologic contributors to the race-associated survival disparity, we propose a complementary approach that addresses major knowledge gaps in our current understanding of AML biology in Black patients, including the overdue characterization of the Black AML genome and subsequent delineation of biologic response to treatment.

Charting the surfaceome to eliminate hairy cell leukemia (HCL)

To optimize treatment of HCL, we dissect the tumors` surface proteome to understand a) surface mediated signals and b) the dependence on BRAFV600E activity, to c) eradicate remaining cell populations after BRAF inhibitor treatment. We use chemoproteomics, which enable mass-spectrometric-based surfaceome discovery to quantitatively investigate HCL. We expect to identify HCL specific and BRAF-dependent surfaceomes and identify new and critical targets for treatment.

A phase 1 study of KT-333, a STAT3 protein degrader, in patients with NHL

In March 2020, LLS made an equity investment in Kymera Therapeutics to "Support Studies with Protein Degraders for Development in Hematological Patients."

Kymera Therapeutics is a clinical-stage biopharmaceutical company founded with the mission to discover, develop, and commercialize transformative therapies while leading the evolution of targeted protein degradation, a transformative new approach to address previously intractable disease targets. Whereas most targeted therapies inhibit or inactivate the proteins or genes that drive the cancer, targeted protein degradation harnesses the body’s natural system of ridding itself of unwanted, “old” or “broken” components of cells.

KT-333 is STAT3 protein degrader and is enrolling NHL patients including T-cell lymphoma (PTCL, CTCL) and LGLL in a Phase 1 clinical trial (NCT05225584).

Validation of Critical 1q21 Vulnerabilities in multiple myeloma

In previous studies of recurrently amplified 1q21 genes in myeloma, we identified ILF2 as a modulator of the DNA repair pathway, which promotes adaptive responses to genotoxic stress. Thus, ILF2 may have clinical utility as a biomarker of aggressive myeloma and blocking the ILF2-mediated repair signaling may enhance the effectiveness of current DNA-damaging agent-based therapies. We are seeking to determine the feasibility of therapeutically targeting ILF2 with antisense nucleotides and identify DNA repair effectors whose loss of function induces synthetic lethality in ILF2-depleted myeloma.

A phase 1 study of CB-011, a CRISPR-edited allogeneic CAR-T targeting BCMA, in patients with multiple myeloma

In February 2021, LLS made an equity investment in Caribou Biosciences to support "A Phase 1, Multicenter, Open-Label Study of CB-011, a CRISPR-Edited Allogeneic Anti-BCMA CAR-T Cell Therapy in Patients With Relapsed/Refractory Multiple Myeloma." 

Caribou is a leading clinical-stage biotechnology company, co-founded by CRISPR pioneer and Nobel Prize winner Jennifer Doudna, Ph.D., using next-generation CRISPR genome-editing technology to develop “off-the-shelf” (allogeneic) CAR therapies for hard-to-treat blood cancers.

CB-011, Caribou’s second allogeneic CAR-T cell therapy, targets BCMA for the treatment of relapsed/refractory multiple myeloma and is immunologically cloaked for enhanced persistence. The CaMMouflage Phase 1 clinical trial, a multicenter, open-label study to evaluate the safety and efficacy of a single dose of CB-011 in adult patients with relapsed or refractory multiple myeloma (r/r MM), is currently enrolling (NCT05722418).

Translational Discovery in Peripheral T-Cell Lymphomas

Peripheral T-cell lymphomas (PTCLs) are poorly understood and patients with PTCL are underserved by current therapies. The most common subtypes (among >20) are PTCL-not otherwise specific (NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large cell lymphoma (ALK- ALCL). Rational treatment strategies for these lymphomas are lacking, largely due to the insufficient characterization of PTCL pathobiology and historic paucity of faithful models. Over the past 4 years, our groups and others have identified recurrent alterations in PTCL subsets, developed targeted agents against PTCL and established an unprecedented repository of PTCL models for in vitro and in vivo interrogation. A clinical trial led by director Dr. Horwitz established a new standard-of-care for upfront treatment of CD30+ PTCLs. Additional trials developed through this SCOR have advanced therapeutics targeting PI3 kinase (duvelisib), JAK1/2 (ruxolitinib) and IDH2 (enasidenib) for relapsed/refractory PTCL. The central goal for the next 5 years of support is to establish informed combination strategies that eradicate resistant populations and thereby extend the duration of meaningful responses.

A phase 1 expansion study of IO-202, an antibody targeting LILRB4, in combination with azacitidine in patients with monocytic differentiation AML and CMML

In March 2021, LLS made an equity investment in Immune-Onc Therapeutics to support the "Phase 1 Clinical Development of IO-202, An Antibody Targeting LILRB4, for the Treatment of AML with Monocytic Differentiation and CMML."

Immune-Onc is a private, clinical-stage cancer immunotherapy company dedicated to the discovery and development of novel myeloid checkpoint inhibitors for cancer patients. The company aims to translate unique scientific insights in myeloid cell biology and immune inhibitory receptors to discover and develop first-in-class biotherapeutics that reverse immune suppression in the tumor microenvironment. Immune-Onc has a differentiated pipeline with a current focus on targeting the Leukocyte Immunoglobulin-Like Receptor subfamily B (LILRB) of myeloid checkpoints. The company’s work builds on early research by Chengcheng (Alec) Zhang, Ph.D. at the University of Texas Southwestern Medical Center that was also funded by LLS grants.

IO-202 is a first-in-class antibody targeting the LILRB4 and has entered a phase 1 cohort expansion clinical trial (NCT0437243) for the treatment of AML (IO-202 in combination with azacitidine) and CMML (IO-202 in combination with azacitidine). 

A phase 3 randomized study of pelabrasib (CPI-0610), a BET inhibitor, and ruxolitinib in JAK inhibitor treatment naive MF patients

In July 2012, LLS began its partnership with Constellation to support three first-in-human Phase 1 clinical trials for blood cancer patients and is currently supporting "A Phase 3, Randomized, Double-blind, Active-Control Study of CPI-0610 and Ruxolitinib vs. Placebo and Ruxolitinib in JAKi Treatment Naive MF Patients."

Constellation Pharmaceuticals was a clinical-stage biopharmaceutical company developing novel therapeutics that selectively modulate gene expression to address serious unmet medical needs in patients with cancer. MorphoSys acquired Constellation in July 2021 and continues to enroll patients with myeloproliferative neoplasms in multiple clinical studies.

Pelabresib (CPI-0610) is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. Pelabresib in combination with ruxolitinib is in a Phase 3 clinical trial (NCT04603495) for myelofibrosis patients that have not been previously treated with Janus kinase inhibitors.

A phase 2 study of AFM13, a bispecific cell engager targeting CD30 and CD16A, in combination with AB-101 (allogeneic natural killer cells) in patients with classical HL and CD30-positive PTCL

In August 2013, LLS began its first European partnership with Affimed that supported two clinical trials for Hodgkin lymphoma (HL) patients. Expanding upon the initial work supported by LLS TAP, Affimed is currently enrolling "A Phase 2 Study of Innate Cell Engager AFM13 in Combination With Allogeneic Natural Killer Cells (AB-101) in Subjects With Recurrent or Refractory Hodgkin Lymphoma and CD30 Positive Peripheral T-Cell Lymphoma."

Affimed is a clinical-stage immuno-oncology company committed to giving patients back their innate ability to fight cancer by actualizing the untapped potential of the innate immune system using the proprietary ROCK® platform to enable a tumor-targeted approach to recognize and kill a range of hematologic and solid tumors.

AFM13 is bispecific tetravalent engager targeting CD30 on tumor cells and CD16A on NK cells and macrophages. AFM13 in combination with AB-101 (allogeneic natural killer cells) is currently in a Phase 2 clinical trial in relapsed or refractory Hodgkin lymphoma or CD30-positive PTCL (NCT05883449).

A phase 1 study of CB-010, a CRISPR-edited allogeneic CAR-T targeting CD19, in patients with B-cell NHL

In February 2021, LLS made an equity investment in Caribou Biosciences to support "A Phase 1, Multicenter, Open-Label Study of CB-010, a CRISPR-Edited Allogeneic Anti-CD19 CAR-T Cell Therapy in Patients With Relapsed/Refractory B Cell Non-Hodgkin Lymphoma."

Caribou is a leading clinical-stage biotechnology company, co-founded by CRISPR pioneer and Nobel Prize winner Jennifer Doudna, Ph.D., using next-generation CRISPR genome-editing technology to develop “off-the-shelf” (allogeneic) CAR therapies for hard-to-treat blood cancers.

CB-010, Caribou’s lead allogeneic CAR-T cell program, targets CD19 and is being evaluated in a Phase 1 clinical trial expansion cohort for second-line patients with large B cell lymphoma (LBCL). (NCT04637763). It is the first clinical-stage allogeneic CAR-T cell therapy in which PD-1 was genetically disrupted in the CAR-T genome, leading to more durable anti-tumor activity in pre-clinical studies.

Development of therapeutic strategy for the treatment of MDS

TP53 mutations are present in 10% of MDS cases and are associated with reduced survival and poor prognosis. However, the effect(s) of TP53 mutations on MDS pathogenesis is unknown. We discovered that MDS cells with TP53 mutations display significant alterations in pre-mRNA splicing due to increased EZH2 activity. We will investigate the mechanisms by which TP53 mutations drive MDS pathogenesis and determine the impact of inhibition of EZH2 and the spliceosome on MDS cells with TP53 mutations.

Dissecting the heterogeneity of leukemic and pre-leukemic clonal expansion to identify genes associated with leukemia relapse and genesis

My research investigates the heterogeneity of leukemic and pre-leukemic clonal expansion to identify genes associated with leukemia relapse and genesis. Contrary to conventional studies analyzing cell mixtures, my research uniquely probes the specific cells underlying leukemia development. We expect to identify the key cellular and molecular events that drive leukemia onset and relapse. These findings will help improve diagnosis and can serve as new therapeutic targets for treating leukemia.

Neonatal origins of pediatric AML

Coming soon.

Personalized Metabolic Targeting of Epigenetic AML Mutations Through the Alpha-Ketoglutarate Pathway

AML is characterized by founder mutations in epigenetic regulators that perturb alpha-ketoglutarate flux to block differentiation and rewire metabolism exposing new druggable vulnerabilities. By integrating bioenergetics and 5hmC profiling in primary cells, we have discovered unexpected 2-hydroxyglutarate-independent vulnerabilities for TET2, IDH1, IDH2, WT1, and CEBPA mutations. Here, we propose mutation-directed drug development for AML through targeting of the alpha-ketoglutarate pathway.

Targeting v-ATPase mutations and activated autophagic flux in follicular lymphoma

In this proposal we seek a mechanistic understanding how mutations in ATP6V1B2 in FL activate autophagic flux and also maintain mTOR in an active state. Given that 25-30% of FL harbor mutations in various v-ATPase subunits and regulators (ATP6V1B2, APT6AP1, VMA21) we will extend our studies to these genes. We will clarify how and under what circumstances activated autophagy can be targeted in FL, why it works, and what the best molecular targets and drugs are.

Novel Immunotherapeutic Development in Childhood AML

Dr. Soheil Meshinchi is taking a personalized medicine approach to identify immunotherapies for specific subsets of pediatric acute myeloid leukemia (AML). Pediatric AML remains a devastating disease with only a 60% survival rate. Survivors often have long-term quality of life issues related to the toxic chemotherapy used to treat their disease. A better knowledge of the molecular basis of pediatric AML will help identify targets for therapeutic intervention. Some of these targets may be mutants of normal genes, while others may be overexpression of normal genes, which would provide a therapeutic window in which targeting the overexpressed gene product may preferentially kill tumor cells. Dr. Meshinchi has surveyed the gene expression spectrum of pediatric AML and has identified several targets which are overexpressed in pediatric AML. One protein, CD74, is highly expressed in a subset of AMLs. Another target is CD70, which is highly expressed in about half of all pediatric AML cases that include a fusion of the MLL protein. Patients with MLL fusions have a worse outcome. Lastly, some infant AML patients have another kind of fusion protein paired with overexpression of the FOLR1 protein. All three proteins that Dr. Meshinchi has identified as being highly expressed in subsets of pediatric AML have much lower expression in healthy cells. Therefore, targeting these proteins is a logical choice. These three proteins are all expressed on the surface of the cell, making them accessible to targeting by special therapeutic antibodies called “antibody drug conjugates” (ADCs). ADCs have a toxic payload attached to them. When the antibody binds to its target on the cell surface, the cell takes in the ADC releasing the toxic payload, which then kills the cell. This immunotherapy approach is a highly specific, personalized approach for treating cancer. ADCs to each of the protein targets identified by Dr. Meshinchi are being clinically evaluated in other diseases, providing the opportunity to potentially repurpose those drugs for pediatric AML. Therefore, Dr. Meshinchi proposes to evaluate these ADCs in laboratory models of pediatric AML. Should any of these drugs show promise in these laboratory models, Dr. Meshinchi will propose clinical trials in pediatric patients through LLS’s Pediatric Acute Leukemia (PedAL) Master Clinical Trial. If any of the targets do not have an effective drug in the laboratory models, Dr. Meshinchi will create new ADCs using proven expertise currently available in his laboratory. Therefore, these studies present the possibility of new, targeted immunotherapy for specific subsets of pediatric AML patients, either rapidly through drug repurposing, or through the development of new ADCs. The goal is to improve the survival and quality of life for these vulnerable blood cancer patients.

Multi-modal Immunotherapeutic Targeting of AML-restricted Targets in Infants and Children

Advances in understanding and management of AML in children has been stagnant for decades. Observed improvements in survival are more directly linked to improvements in supportive care or risk identification rather than advances in therapeutics. Excitement around FDA approval of two new IDH1/2 inhibitors did not reach the pediatric oncology community given paucity or absence of such mutations in children. This also highlights the stark differences between AML in older adults and that in younger patients. Thus, “trickle down therapeutics” where therapies that are developed in older adults are used effectively in children is a flawed concept. Discoveries and therapeutic development in younger patients must be prioritized if meaningful advances are to be made in curing AML in younger patients. Given that AML in children is not a priority for the pharmaceutical companies, alternate mechanisms for advancing therapeutics in children and young adults should be implemented.

Delivering unique immunotherapeutics for treatment of mantle cell lymphoma

City of Hope has a reputation for innovative translational research, and multiple researchers in the proposed application are prominent in the lymphoma field. The institutional commitment to translational science is evident in City of Hope’s investment in research support/regulatory affairs infrastructure and campus GMP manufacturing facilities. Since patients with mantle cell lymphoma (MCL) have poor outcomes after autologous transplantation, our researchers have been developing new immunotherapeutic strategies to combat this disease. This RFA was timely, as our team was preparing several innovative projects specifically focused on MCL. Our projects are unified by a focus on specific cell and pathway targeting, and antibody-based biologic agents. In fact, 3 of the proposed agents to be tested in this grant were developed here and will be manufactured at City of Hope. The immunotherapies proposed here target a range of antigens, including a unique MCL-specific antigen, and employ novel mechanisms of action, including B-cell receptor (BCR) feedback control, T cell killing and antibody-dependent cytotoxicity. Tumor target specificity is crucial to the safety and tolerability of any immunotherapy. However even with perfect specificity, targeting a single antigen or pathway is frequently insufficient due to antigen- and immune-escape mechanisms. Therefore we are exploring combining our antibody-based agents with inhibitors of B cell signaling (BTK, PI3K, Akt), as well as combining them between projects, in order to cut off tumor escape routes. Developing therapeutics with both high specificity and high potency against MCL is a lofty goal, but one that we aim to achieve. Project 1: Development of a unique tumor-specific, antibody therapy against mantle cell lymphoma (L Kwak, H Qin, L Chen). We have utilized a live cell-based phage display platform to target low-abundance, unique cell markers, discovering an antibody light chain binding domain specific to human MCL. We have further engineered a light chain antibody that binds highly specifically to MCL (MCLC-Ab), with no binding to other subtypes of B-cell lymphomas, nor to normal blood cells. This MCLC-Ab shows potent anti-tumor activity in xenograft MCL models. In Project 1, we will identify the MCLC-Ab target and confirm the antibody specificity for MCL by immunohistochemistry and flow cytometry (SA1). The MCLC-Ab will then undergo preclinical development as both an MCL diagnostic antibody (SA2) and as a potent, MCL-specific therapeutic (SA3). Project 2: Combining CAR T cells with signaling modulators for treatment of relapsed/refractory mantle cell lymphoma (S Forman, X Wang, E Budde, S Blanchard). CD19 chimeric antigen receptor (CAR) T cell therapy is limited by suboptimal response rates in non-Hodgkin lymphoma (NHL), persistent B cell aplasia, and a high risk of cytokine release syndrome (CRS). To improve the remission rates for patients with MCL, we propose combining CAR T cells with 3 oral agents that modulate B and T cell signaling: the BTK inhibitor ibrutinib, the Akt inhibitor MK-2206, and the PI3K inhibitor TGR-1202. First we propose a clinical trial of ibrutinib for relapsed MCL, followed by CD19CAR T cell infusion (SA1). We expect that ibrutinib will enhance response rates to CAR T cell therapy and may also decrease cytokine production, reducing severe CRS. This trial is built on our established clinical platform for CD19CAR T cell therapy for NHL. We will also optimize and pre-clinically develop the MCLC-Ab from Project 1 as a CAR, with the potential to avoid persistent B cell aplasia (SA2). Finally, we plan to test the use of Akt and PI3K inhibitors as part of CAR T cell manufacturing to improve T cell persistence and potency, and in vivo as combined therapy with CAR T cells (SA3). Project 3: Targeting oncogenic B cell receptor (BCR)-feedback control in refractory mantle cell lymphoma (M Muschen, V Ngo, R Chen, L Chen). Project 3 proposes to target the CD25 surface antigen present on both regulatory T cells (Tregs) and MCL cells, using a new CD25 antibody-pyrrolobenzodiazepine conjugate (ADCT-301). In SA1, in a humanized mouse model, we will use the CD25-ADC to pre-deplete immunosuppressive Tregs and enhance the activity of Project 1’s MCLC-Ab and Project 2’s CD19 CAR T cells. We have discovered that MCL cell surface CD25 recruits inhibitory SHIP1, attenuating oncogenic BCR signaling strength. CD25 normally cycles from cytoplasm to surface of MCL cells, but can be forced to remain on the cell surface via CD19 engagement or PI3K/Akt inhibition. In SA2, we will combine CD19 antibody or CD19 CAR T cells with CD25-ADC to force CD25 surface expression, enhancing ADCT-301 targeting. In SA3, we will stimulate CD25 surface accumulation using Akt and PI3K inhibitors to maximize targeting. Core A: Pathology and Tissue Bank Core (WC Chan, J Song). Core A will provide tissue bank services, screen MCLC-Ab to validate its specificity (FFPE sections, flow cytometry) and diagnostic utility (Project 1), provide MRD and residual tumor assessment for the clinical trial (Project 2), and assess immune reconstitution in humanized mice (Project 3). Core B: Translational Core (S Thomas, C Matsumoto). Core B will provide project management, clinical trial design, clinical protocol development, IND preparation, scientific writing and regulatory support services. Synergy: Our researchers are extremely collaborative as evidenced by the interactions that weave the individual projects into a cohesive team-science program. Project 1 + Project 2: Development of MCLC-CAR T cells. Project 2 + Project 3: CD19 stimulation of CD25 surface expression prior to ADC therapy, PI3K/Akt inhibition studies. Project 3 + Project 2 + Project 1: Regulatory T cell depletion with CD25-ADC prior to CAR T cell therapy or MCLC-Ab. Core A and Core B will provide services for all 3 projects as described above.

Structural chromosomal rearrangements and the multi-step progression of multiple myeloma

Two newly identified structural DNA changes, termed chromothripsis and chromoplexy, result in the formation of new chromosomal structures where multiple genes can be deregulated simultaneously. These events involve the relocation of super-enhancers to the sites of oncogenes, which provides a strong drive for cancer progression, an association with high-risk status, adverse prognosis, and punctuated evolution.

Synergistic targeting of metabolic and epigenetic vulnerabilities in leukemia stem cells

Our lab is focused on identifying unique features that distinguishes acute myeloid leukemia (AML) stem cells from normal blood-forming stem cells. The cells that make more AML cells than others are called AML stem cells, and these cells need to be eradicated to achieve deep therapeutic responses. We believe targeting metabolism may achieve this goal and found strategies to target AML stem cell metabolism without harming normal stem cells. We hope that our study will lead to improved therapies against AML targeting metabolism to achieve deep remission with little toxicity.

CD79b as a novel target for CAR T-cell therapy in B-cell malignancies

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 induces durable remissions in a significant proportion of patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphomas (NHL). However, relapse or progression occurs in ~60% of patients with majority of them experiencing CD19 loss in their tumors. Here, we will characterize the mechanism of CD19 loss in NHLs and develop CD79b CAR T-cell therapy as a novel approach to overcome CAR T resistance due to CD19 loss.

Delineation of the molecular heterogeneity underlying treatment failure in follicular lymphoma

A proportion of follicular lymphoma patients will experience early treatment failure and premature death. We will delineate the molecular features that underlie treatment failure from a recent randomized trial (BIONIC) & Canadian cohort via 3 aims: 1) confirm the prognostic significance of prior reported biomarkers (eg, m7-FLIPI, etc); 2) establish the genetic taxonomy of FL via integrated genomic analyses and consensus clustering; and 3) determine the prognostic value of circulating tumor DNA.

The role of truncating ASXL1 mutations in disease initiation and progression of human myeloid malignancies

N/A

SCOR in High Risk Plasma Cell Dyscrasias

Dr. Orlowski assembled an experienced, collaborative group of researchers who work in a multidisciplinary manner on projects focusing on basic, translational, and clinical aspects of smoldering multiple myeloma (SMM) and multiple myeloma (MM). Both high risk SMM and MM represent important and urgent unmet medical needs for the development of novel, more effective therapies.

Studying the biology and therapeutic vulnerabilities of leukemia stem cells using AML-iPSCs

Acute myeloid leukemia (AML) is an aggressive blood cancer that still lacks effective therapies. Our goal is to identify therapeutic vulnerabilities for long-lasting remission or cure of AML by targeting the leukemia stem cells (LSCs), the cells that maintain the disease and re-grow it upon relapse. To this end, we leverage unique model systems of AML LSCs that we have developed using induced pluripotent stem cell (iPSC) technology. Our study may open new avenues for the therapy of AML.

Targeting kinase-dependent dysregulation of transcription factor control in acute myeloid leukemia

Defining mechanisms of dysregulated gene control are central to understanding cancer and the development of effective therapies. Our research is focused on the mechanisms of gene control dysregulation in acute myeloid leukemia (AML), a refractory form of blood cancer that affects both children and adults. Using new methods for manipulating proteins, we are defining essential mechanisms by which AML cells enable cancer-causing gene expression. This work also allowed us to develop new drugs to specifically block this in cancer, but not healthy cells. Ongoing work aims to define precise mechanisms of cancerous gene control and develop definitive treatments for its control.

Targeting DCAF1 as a novel treatment strategy for therapy resistant multiple myeloma

We have identified the multi-domain protein DCAF1 as a genetic dependency in multiple myeloma and developed a series of potent on-target DCAF1 inhibitors that have a unique mode of action compared with existing therapies. In this proposal we will continue the detailed molecular characterization of our lead compound Vpr8. In parallel, using Vpr8 as the scaffold, we will develop a new series of PROTAC drugs that engage the ubiquitin ligase activity of DCAF1-containing E3 complexes.

Pan-heme CAR: Anti-CD38 CAR T cells for myeloid, lymphoid and plasma cell malignancies

Our SCOR team has a razor-sharp focus on an exciting new treatment modality for blood cancers: chimeric antigen receptor (CAR) T cells. T cells can be trained to target cancer cells by genetic modification. In fact, previous support from the Leukemia & Lymphoma Society allowed us to successfully develop CAR T cells targeted to CD19, a pan-B cell marker. This treatment, generically called CART-19, was approved by the FDA in 2017 for the treatment of B-cell acute lymphoid leukemia (B-ALL) and in 2018 for some non-Hodgkin lymphoma (NHL), with promising results in other B cell malignancies such as chronic lymphocytic leukemia (CLL). Thus, the development of a single therapy for a single disease (initially, CLL) paid handsome dividends when translated to a broader range of CD19-expressing malignancies (ALL, NHL).

Dissecting the role of a key epigenetic modulator in Mixed Lineage Leukemia

We study how a protein called Dpy30 controls blood cancers by regulating chromatin, the physical structure where our genes reside. We study how this protein controls addition of a specific chemical group onto chromatin, thereby regulating expression of genes for leukemia in cells and animals. We are also developing chemicals to inhibit Dpy30’s activity in leukemia. We hope to better understand the role of Dpy30 in leukemia and identify Dyp30-inhibiting chemicals for leukemia treatment.

Targeting Leukemia Stem Cells in the Clinical Setting: The Development of A Comprehensive Program

My focus is to develop a program in which novel therapies targeting leukemia stem cells (LSCs) are tested in clinical trials. This is achieved via partnership with laboratory-based colleagues who identify vulnerabilities in LSCs. Once recognized, we find or develop drugs to exploit these weaknesses through clinical trials for acute myeloid leukemia patients. The goal is to bring forward new therapies that result in deep and durable responses, which also have the potential to cure this disease.

The role of FOXM1 downregulation in the development of clonal dominance in del(5q) MDS

Our research focuses on identifying the molecular mechanism underlying the development of a dominant population of abnormal stem cells in myelodysplastic syndrome (MDS) patients. We will employ mouse genetic models and MDS patient samples to elucidate the role of FOXM1 in the development of a dominant population of abnormal stem cells in vivo. This research program may lead to the identification of new effective therapeutic strategies for the treatment of early stages of MDS patients.

Targeting Plek2 for the treatment of myeloproliferative neoplasms

Current therapy for MPNs remains suboptimal with ongoing risks for thrombosis. Newer drug such as JAK inhibitor has toxicity and is not curative. New targeted therapy with less side effects is urgently needed in the field. This project focuses on the inhibitors of Plek2, a novel target of MPNs. We have identified lead compounds of Plek2 through screening and medicinal chemistry. We propose to further study the mechanisms of action of the inhibitors and perform in vivo studies using MPN models.

Detection and Targeting of Enzymatic Base Editing Deregulation in Leukemia Stem Cells

Dr. Jamieson is examining the role of two enzymes (APOBEC3 and ADAR1) known to mutate DNA and RNA, and their role in acute myeloid leukemia (AML) and disease relapse, particularly in elderly patients.

Improving BTK Inhibitor Therapy in Chronic Lymphocytic Leukemia Through Rational Combination Strategies

Ibrutinib is a targeted oral treatment for CLL that is safe and highly effective, however it must be given indefinitely which leads to chronic side effects and allows resistance to develop. We are conducting two clinical trials that add a second drug to ibrutinib to eliminate the remaining leukemia or ibrutinib-resistant leukemia cells. If these trials are successful, people taking CLL with or without resistance may be able to stop treatment in remission after taking an ibrutinib combination.

Immunotherapy of Hematologic Malignancies

The overall goal of this SCOR proposal is to develop and clinically validate T-cell immunotherapies designed to produce antitumor activity without the toxicities associated with intensive chemotherapy. The effectiveness of T-cell immunotherapy for leukemia and lymphoma has now been amply demonstrated. Studies conducted in our previous SCOR have already led to multicenter trials and orphan drug designation of EBV-specific T cells for the treatment of EBV-positive NHL and to commercial licensing of our genetically modified T cells and a genetic safety switch engineered into effector T cells.

Engineering nanobodies for lymphoma immunotherapeutics

This project will generate optimized single-chain antibodies (nanobodies) against HVEM and BTLA, two cell receptors that are misregulated in ~75% of follicular lymphomas. We will select for nanobodies that inhibit lymphoma tumor growth through restoration of HVEM or BTLA activity. We will further engineer lymphoma-targeted CAR-T cells, which have shown anti-tumor activity in other malignancies, to secrete these anti-HVEM or anti-BTLA nanobodies, in an alternative combination therapy approach.

Manipulation of cell fate in myeloid disease

Apoptosis is a normal cellular process of getting rid of extra cells that is co-opted by cancer cells to enhance their own survival, and we aim to better understand this process in myelodysplastic syndromes (MDS). Pevonedistat (PEV) is a novel therapy presumed to function, in part, through its effects on apoptosis. Our clinical trial will combine PEV with the standard of care therapy for MDS, azacitidine, in order to keep cancer cells from hijacking apoptosis, and we will study patient samples to match responses with molecular changes in the cancer cells. We seek to determine the suitability of this approach for MDS, and the ability to predict which patients may respond to PEV-based therapy.

T cell acute lymphoblastic leukemia accumulation in the central nervous system

T cell acute lymphoblastic leukemia (T-ALL) has a strong tendency to infiltrate the central nervous system (CNS). The goal is hope to develop strategies to treat CNS disease in T-ALL with less neurotoxicity and more efficacy than current chemotherapy.

Deciphering the metabolic basis for t(11;14) multiple myeloma venetoclax sensitivity

The BCL-2 antagonist venetoclax is highly cytotoxic in a subset of t(11;14) multiple myeloma (MM). In investigating the metabolic basis for the sensitivity of t(11;14) MM to venetoclax, we determined that sensitive cells exhibit significantly reduced succinate ubiquinone reductase (SQR) activity. In addition, inhibition of SQR sensitizes resistant MM to venetoclax. Our proposal seeks to investigate SQR as a diagnostic and therapeutic target to broaden the application of this potent BH3 mimetic.

Novel combination strategies to enhance brentuximab vedotin efficacy in relapsed/refractory Hodgkin Lymphoma

New, non-chemotherapy treatments that use a patient’s own immune system have transformed the treatment of Hodgkin lymphoma (cHL). Typically used in patients with cHL that is resistant to standard treatment, these immune therapies can control the disease for months to years. However, in the long run, most patients will not be cured and will have immunotherapy-resistant cHL. My research evaluates strategies for reversing resistance to brentuximab vedotin (BV) immunotherapy for cHL by combining BV with other treatments in clinical trials.

Role of ERK isoforms in normal hematopoiesis and leukemia

Current therapies for cancers driven by “RAS/ERK’ pathway mutations, such as juvenile myelomonocytic leukemia (JMML), are either high risk (bone marrow transplant) or ineffective (targeted inhibitors). We have identified a unique dependency of JMML cell growth for a group of ERK targets, which are not required for normal blood cell growth. We are investigating this further and aim to identify the ERK targets responsible, which may provide new drug targets to treat JMML and other cancers.

Preclinical optimization of statin/BH3 mimetic combinations in multiple myeloma

This project will evaluate a novel two-drug combination to improve killing of multiple myeloma (MM) cells. First, we will test the hypothesis that statins increase killing of MM cells by BH3 mimetics including venetoclax and the MCL-1 inhibitor AMG 176. Second, we will identify biomarkers that predict response. This project will have significant positive impact on two fields: repurposing statins for blood cancer, and application of BH3 mimetics to improve health and survival of MM patients.

Targeting Enhancer Dysfunction in Hematological Malignancy

Blood cancers such as leukemia, lymphoma and myeloma may be caused by abnormal regulation of genes that control normal cell growth and development. Genes that are normally active can be silenced and/or genes normally not present in a blood cell are abnormally activated. The result can be an uncontrolled signal for continued cell growth or survival. Our group studies the molecular basis of this gene deregulation using cells cultured in the laboratory, human specimens, and animal models.

Targeting cathepsin G in acute myeloid leukemia

We developed a chimeric antigen receptor (CAR) targeting an epitope of the myeloid associated antigen cathepsin G that is processed and presented in the contest of the MHC complex in myeloid leukemic cells. T cells expressing the cathepsin G specific CAR (CG1.CAR) recognize HLA-A2+ myeloid target cells expressing cathepsin G. We intend to study efficacy and safety of CG1.CAR-T cells in preclinical models in preparation of a phase I clinical study in patients with relapsed/refractory AML.

Targeted therapy for AML expressing mutant RUNX1

Clinical outcome of high-risk Myelodysplastic Syndrome (MDS) and AML with mutant (mt) RUNX1 is relatively poor. Supported by our preclinical data, we propose a Phase Ib clinical trial of omacetaxine mepisuccinate (OM) and venetoclax along with correlative science studies in patients with relapsed MDS or AML exhibiting mtRUNX1. Studies proposed will also determine pre-clinical activity of novel, OM-based combinations against mtRUNX1-expressing, patient-derived, pre-treatment AML cells.

Improving risk assessment of AML with a precision genomic strategy to assess mutation clearance

We will enroll transplant-eligible patients with intermediate-risk AML, and define mutation clearance after recovery from induction using deep exome sequencing. Patients who clear all mutations will be consolidated with chemotherapy only (HiDAC). Patients who fail to clear all mutations will be offered an allogeneic transplant. This prospective study may improve outcomes for intermediate-risk patients by more precisely using transplantation in first remission.

Enhancing efficacy of cyclin-dependent kinase inhibitors in diffuse large B-cell lymphoma

Nearly half of patients with diffuse large B-cell lymphoma (DLBCL), ultimately fail current therapies and die from their disease. Selective targeting of cyclin-dependent kinase 9 (CDK9) is a promising strategy, as evidenced by potent anti-tumor effects in preclinical models of DLBCL. Yet tumors evade therapy by developing resistance. This proposal seeks to both elucidate and circumvent the oncogenic events underlying this resistance in order to offer novel therapeutic approaches to treat DLBCL.

Therapeutic modulation of serine availability for SF3B1-mutant myeloid malignancies

Mutations in the spliceosome gene SF3B1 are common in myeloid malignancies, but they are currently untargetable. Our previous work has shown that SF3B1 mutations reprogram energy metabolism and create vulnerability to restriction of the nonessential amino acid serine. Here we propose a preclinical project studying PEGylated cystathioinine beta synthase (pCBS), a recombinant enzyme that catabolizes serine, as a treatment for SF3B1-mutant myeloid malignancies.

Identification of novel therapeutic strategies for aggressive subtypes of CTCL

Coming soon.

Longitudinal functional genomics in mantle cell lymphoma therapy and drug resistance

Overview Title: Longitudinal functional genomics in mantle cell lymphoma therapy and drug resistance Weill Cornell Medicine and Ohio State University PI: Selina Chen-Kiang, Ph.D. co-PI: Peter Martin, M.D. Despite the plethora of therapies available for mantle cell lymphoma (MCL), it remains incurable due to the development of drug resistance. Moreover, each successive treatment failure is associated with a more rapidly proliferating disease and fewer practical treatment options. For example, the BTK inhibitor (BTKi) ibrutinib has unprecedented activity but failure is virtually universal and is associated with dismal outcomes. Understanding the genomic basis and mechanisms for drug resistance in MCL is therefore urgently needed. Our goal is to develop superior therapies for MCL that are practical, well tolerated and amenable to patient stratification, by defining the genomic and the molecular and immunological mechanisms for drug resistance in the context of rationally designed clinical trials with targeted agents. Targeting the cell cycle represents a rational approach to MCL therapy, as dysregulation of CDK4 and aberrant cyclin D1 expression underlie unrestrained proliferation in disease progression. We have demonstrated that induction of prolonged early G1 arrest (pG1) by inhibiting CDK4 with palbociclib not only prevented proliferation of primary MCL cells but also reprogrammed them for killing by clinically relevant targeting agents including ibrutinib and PI3K inhibitors (PI3Ki)s. By longitudinal functional genomics of serial biopsies from MCL patients treated with either palbociclib or ibrutinib we discovered a close association of clinical response with inactivation of PI3K and activation of the tumor suppressor transcription factor FOXO1. Moreover, chromatin remodeling appeared to be the proximal event that reprograms MCL cells in response to CDK4 inhibition. Collectively, our findings suggest that through regulation of PI3K and FOXO1 and the epigenome, induction of pG1 by CDK4 inhibition reprograms MCL for a deeper and more durable clinical response to BTKi and PI3Ki. Supporting this hypothesis, in our phase 1 clinical trial of palbociclib + ibrutinib (PALIBR) in recurrent MCL (N=27) the overall response rate was 67% with 43% complete responses. The responses were rapid and durable; only 2 responding patients have progressed in the 32 months since the trial opened. To further accelerate the development of targeted MCL therapies, we have developed a novel inhibitor for protein arginine methyl transferase 5 (PRMT5), which is dysregulated in MCL and many other human cancers. Inhibition of PRMT5 reverses PRMT5 catalyzed epigenetic marks, restores regulatory pathways and enhances survival of preclinical models of MCL and kills ibrutinib-resistant primary MCL cells. Building on these novel findings and capitalizing on the upcoming multi-center phase 2 PALIBR in recurrent MCL, we propose to investigate drug resistance and develop new strategies that circumvent drug resistance in three integrated projects. Project 1: Development of rational treatment strategies for new and recurrent MCL (PI: Peter Martin, M.D.; co-PI: Jia Ruan, M.D., Ph.D., and Kami Maddocks, M.D.). We aim to develop regimens that can be targeted to the appropriate patient subset, are well tolerated, and can be administered in the community. We will conduct a multicenter feasibility trial of lenalidomide + rituximab (R2)+ durvalumab in untreated MCL with real-time monitoring of MRD. We will explore whether durvalumab can overcome immune-mediated resistance to R2 and whether using MRD to modify therapy improves tolerability and practicality without compromising efficacy. We will also conduct a multicenter phase 2 trial of PALIBR in previously treated MCL to better define patients most likely to benefit from this therapy while providing information on mechanisms of resistance in collaboration with Project 2 and 3. Project 2: Functional genomics and mechanism of drug resistance in MCL (PI: Selina Chen-Kiang, Ph.D.; co-PI: Olivier Elemento, Ph.D., and Lewis Cantley, Ph.D.) The clinical response from the phase 1 clinical trial of PALIBR supports our hypothesis that induction of pG1 by CDK4 inhibition reprograms MCL for a deeper and more durable clinical response. To understand the underlying mechanism, we aim to identify the genomic resistance biomarkers by longitudinal functional genomics in the context of the clinical response to PALIBR in the phase 2 clinical trial in collaboration with Project 1. We will further elucidate the mechanism of pG1 reprograming for ibrutinib vulnerability, and target the therapy vulnerability conferred by the genomic resistance biomarkers discovered in this study, such as targeting PRMT5 in collaboration with Project 3. Project 3: Targeting the epigenome in MCL (PI: Jihye Paik, Ph.D., co-PI: Robert Baiocchi, M.D., Ph.D.). Based on our collective evidence, we hypothesize that dysregulation of PRMT5 and FOXO1 causes epigenetic and gene expression changes promoting MCL proliferation and survival. Thus, targeting PRMT5-regulated epigenome may restore FOXO1-mediated cytotoxic gene expression and induce MCL killing. Our goal is to characterize the epigenetic recruitment of PRMT5 and FOXO1 for mechanism-based targeting of MCL epigenome. We aim to identify direct targets of PRMT5 necessary for MCL proliferation and survival, and to define the role of FOXO1 in killing of MCL cells by targeting the epigenome, in collaboration with Projects 1 and 2. These innovative studies are supported by the Administrative Core, Pathology Core and Genomics, Bioinformatics & Biostatistics Core (organization table appended). In addition, WCM has pledged a match of 1.7 million for the proposed studies as indicated in the letters from Drs. Augustine Choi, Dean of WCM, John Leonard, Interim Chairman of Medicine and Lewis Cantley, Director of the Meyer Cancer Center (appended).

Aberrant LZTR1 and RIT1 signaling as a driver of clonal hematopoietic disorders

Our research focuses on a novel mechanism of RAS protein regulation via the protein LZTR1, which is altered in leukemia and hinders the effectiveness of leukemia therapies. We will utilize mouse models and functional genomic studies to uncover how altered RAS degradation drives leukemia and identify novel drug targets. This effort will help us identify the clinical impact of alterations in this novel RAS pathway in patients and potential means to improve leukemia treatment.

Synergism of cell-intrinsic and cell-extrinsic factors in the clonal evolution of pre-malignant HSCs

We study the mechanisms of clonal hematopoiesis (CH), a process by which mutations provide hematopoietic stem cells (HSCs) with a fitness advantage. CH can precede the development of blood cancer. We use cutting-edge techniques to understand the effects of these mutations on HSC behavior. Our long-term goal is to identify ways to inhibit the growth of these mutant HSCs while sparing normal HSCs in people with CH. This may someday provide a blood cancer prevention method by eliminating the cells which carry the initial cancer-driving mutations.

Modulating Signaling Pathways in Endothelial Cells to Abate Leukemic Progression

We seek to elucidate the mechanisms by which aging of the vascular system contributes to the decline in blood stem cell function and leads to diseases such as hematopoietic malignancies. We have developed novel model systems that have led to the discovery of rejuvenation factors that can restore the functional capacity of an aging blood and vascular system. These studies lay the foundation for the development of therapeutic strategies to not only rejuvenate an aged blood system, but to also give a competitive advantage to non-malignant blood cells while directly targeting cancer cells following chemotherapy regimens commonly utilized to treat hematological malignancies.

Precision medicine-guided drugging of DNA repair to induce synthetic lethality in AMLs

We will test if Gene Expression and Mutation Analysis (GEMA) could be applied as personalized medicine tool to identify individual patients with AML displaying specific preferences for repairing spontaneous and drug-induced DNA damage. These preferences will predispose leukemia stem and progenitor cells to synthetic lethality triggered by already approved as well as novel DNA repair inhibitors.

Rational therapeutic targeting of oncogenic immune signaling states in myeloid malignancies

Dr. Starczynowski is investigating the role and potential benefit of therapeutic targeting of a protein called UBE2N in acute myeloid leukemia (AML).

Pediatric AML PDX Models and Drug Testing-Gateway to Novel PedAL Trials

Pediatric AML is a disease with poor outcomes and a need for improved therapeutic options. Pediatric AML is characterized by diverse lesions that often do not overlap with adult AML, which therefore means therapeutic development must be done using pediatric AML models. Recent advances in patient derived xenograft (PDX) modeling have made possible the successful development of PDX models of diverse pediatric AML subtypes.

Precision Medicine Inhibitor and Immunotherapy Approaches for High-Risk Childhood Leukemias

Dr Tasian’s scientific passion is successful development of precision medicine therapies for high-risk childhood leukemia. Her translational laboratory research program focuses upon investigation of kinase inhibitors and chimeric antigen receptor (CAR) T cell immunotherapies in childhood ALL and AML using primary patient specimens and patient-derived xenograft models. Through her laboratory and clinical research, she aspires to improve cure rates and minimize toxicities for children with leukemia.

BRAF inhibition as an alternative to chemotherapy in the treatment strategy of hairy cell leukemia

Hairy cell leukemia (HCL) is very sensitive to chemotherapy, whose toxicity to the bone marrow and the immune system is however concerning. We have established vemurafenib plus rituximab as a very effective chemotherapy-free regimen in relapsed/refractory HCL (NEJM, in press). Here, we will test it in a clinical trial against a chemotherapy-based standard of care represented by cladribine plus rituximab, aiming at lower toxicity and similar efficacy.

EBV promotes Burkitt's lymphoma progression through microprocessor sequestration.

This proposal aims to understand the molecular mechanisms underlying response to AZA therapy in MDS, as a basis for developing more effective therapies. A ribonucleotide, AZA’s effects on RNA remain unknown. Here, we will investigate the impact of in vivo AZA therapy on RNA alternative splicing and DNA demethylation in MDS patients. Secondly, we will investigate whether AZA treatment exposes neoepitopes in the dysplastic cells of patients, which could be exploited for cancer immunotherapy in MDS

Loss of the non-canonical BAF complex as a driver and therapeutic target in SF3B1-mutant MDS and leukemia

The most common cause of MDS is a genetic mutation occurring in blood cells that affects a process called “RNA splicing”. The most commonly mutated RNA splicing factor gene is called SF3B1. We now know that many patients with MDS carry mutations in SF3B1 but we do not know why these mutations cause disease. Dr. Bradley proposes to determine how mutations in SF3B1 cause MDS and potentially create new opportunities for treating this disease.

The oncogene eIF4E coordinates extracellular signalling in AML

The oncoprotein eIF4E is dysregulated in many cancers including AML. We show that eIF4E drives production of the glycosaminoglycan hyaluronan (HA). Further, HA elevation alters the surface architecture of high-eIF4E AML cells and this is required for eIF4E’s oncogenic activity. We will explore HA’s involvement in AML and the efficacy of depleting HA in patients using hyaluronidase in a Phase I trial in AML.

Targeting non-genetic mechanisms of therapeutic resistance in Acute Myeloid Leukaemia

Drug resistance in AML can develop via a non-genetic process which remains poorly understood. Using our novel cellular barcoding technology that can trace the growth of thousands of cancer cells, our research will identify genes that are switched on or off in AML cells that lead to drug resistance and relapse. This work will reveal the factors underpinning non-genetic drug resistance that may be targeted with new drugs to prevent relapse and ultimately improve quality of life and survival.

Gut microbiota modulation to prevent progression of smoldering multiple myeloma to active disease

Blocking the progression of smoldering multiple myeloma (SMM) to active MM is an unmet clinical need. In primary mouse models of MM, we aim at demonstrating that modulation of the gut microbiota by vaccination against the commensal Prevotella heparinolytica and/or colonization by P. melaninogenica, also in combination with anti-PD-L1 antibodies, inhibit the progression of asymptomatic MM to full-blown disease. Our findings are expected to provide the ground for clinical trials in SMM patients.

Evaluating a novel collaboration between NOTCH1 and MLL1 for improved targeted treatments in T-ALL

Most T cell acute lymphoblastic leukemia (T-ALL) patients respond to chemotherapy, however many relapse with limited therapy options. To address this problem, we are utilizing a newly-developed human T-ALL system to study two potential therapy targets (NOTCH1 and MLL1) and their interaction, to determine if they can be co-inhibited to eradicate disease. Since compounds that inhibit NOTCH1 and MLL1 are already in development, this novel combination strategy could lead to clinical approval sooner.

Targeting immune checkpoint protein B7-H3 (CD276) in acute myeloid leukemia

We found that immune checkpoint protein B7-H3 is overexpressed in Acute Myeloid Leukemia (AML) cells compared to normal hematopoietic cells. We have developed four monoclonal antibodies (mAbs) which successfully block B7-H3 and activate NK cells to induce apoptosis in AML cells. In this proposal we propose to generate therapeutically relevant anti-B7-H3 chimeric recombinant mAbs and test their activity in vivo. In addition, we will identify the receptor for B7-H3 expressed on NK cells.

XPO-1 as a novel therapeutic target in GATA-3 expressing mature T-cell lymphomas

GATA-3 identifies high-risk subtypes of mature T-cell lymphomas (MTCL), as its target genes, which we have systematically identified, have significant cell-autonomous and non-cell-autonomous (by regulating constituents of the tumor microenvironment) roles in these MTCL. As our preliminary data suggests that XPO-1 inhibition is a novel, and largely unexplored, therapeutic strategy in these MTCL, we will examine its cell-autonomous (Aim #1) and non-cell-autonomous (Aim #2) role in GATA-3+ MTCL.

Overcoming BTK Inhibitor Resistance in Chronic Lymphocytic Leukemia

Coming soon.

Restoring lymphoma immunosurveillance by combined EZH2 inhibition and immunotherapy

The project builds on evidence that mutations leading to persistent EZH2 activation drive germinal center B-cell lymphomagenesis by disrupting T-cell surveillance, and will test the hypothesis that EZH2 inhibition synergizes with immune checkpoint blockade and/or co-stimulation to eradicate these diseases. These results will provide the rationale for clinical development of precision-medicine immune-epigenetic combination therapies for lymphomas where these mechanisms are specifically altered.

Testing targeted therapy in LCH

We propose to the hypothesis that patients with LCH who fail initial chemotherapy will respond to a targeted strategy of blocking MAPK signaling through MEK inhibition.  This trial is a Phase 2 study to evaluate the safety and efficacy of cobimetinib in patients with refractory LCH.  Exploratory aims will evaluate response of lesions with specific mutations, ability of peripheral blood mononuclear cells to determine disease burden, and development of somatic mutations in patients who relapse.

Refining Molecular Risk Prediction & Individualized Lymphoma Therapy Using Circulating Tumor DNA

My group studies variation in clinical outcomes of patients with aggressive lymphomas and tries to capture the underlying basis for this variation. We then integrate insights from our studies into molecular prediction tools that inform the probable outcomes of individual patients when treated with therapeutic regimens that are currently available. We hope to build precise risk models that have high predictive value for clinical outcomes of patients with lymphoma. Our goal is to use these models to inform therapeutic trials of novel strategies to improve the outcomes of blood cancer patients.