Research We Fund

A phase 1/2 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 I/II trial has been initiated to assess the safety and efficacy of DR-01 in previously treated LGLL patients.

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.

Increasing access to blood cancer care in Colorado and surrounding regions

The University of Colorado (CU) Division of Hematology/UCHealth Blood Disorders Center (BDCTC) is the only academic program serving patients with hematologic malignancies in the Rocky Mountain Region. This program sees ~1000 new patients annually and operates a dedicated Hematology Clinical Trials Unit (HCTU) that provides clinical trials to persons throughout the Rocky Mountain Region and beyond. Despite opening many clinical trials, it is clear that underserved populations (economically disadvantaged, rural, and/or underrepresented minorities) have low levels of trial enrollment. It is also clear that more proactive efforts are needed in order to more effectively deliver the therapeutic benefits of clinical trials to underserved populations. In order to accomplish this goal, we propose to work with regional community oncology centers on three complementary efforts to increase enrollment of underserved populations throughout the Colorado front range major population centers (metro Denver, Fort Collins, Colorado Springs) as well as rural Colorado and the Rocky Mountain region.

Role of the AML "Immunome" in response and failure of chimeric antigen receptor T cell therapy

Most patients with acute myeloid leukemia (AML) are not cured with chemotherapy alone, and most long-term survivors of AML have undergone an allogeneic stem cell transplant (also known as bone marrow transplant). The outlook is quite grim for patients whose AML relapses after transplant. We have developed a new type of treatment for AML called chimeric antigen receptor (CAR) T cells for these patients. The goal of this project is to investigate how to improve CAR T cells for AML.

Dissect the function of histone demethylase KDM5 on overcoming drug resistance toward immunotherapy in multiple myeloma

We identified that KDM5 can regulate important transcription factors in multiple myeloma (MM) and regulate the bone marrow (BM) microenvironment in providing protection toward MM, which also reduces anti-MM immunity. Thus, our study will utilize our novel potent and selective KDM5 inhibitor to fully dissect the interactions between MM cells, the BM microenvironment and the immune system in cellular and animal models to establish important mechanistic insights into MM.

Role of Health Insurance and Medicaid Expansion in Racial Inequity in Patterns of Care and Outcomes in Multiple Myeloma

Multiple myeloma is the most common blood cancer in African Americans. Thanks to advances in treatment, over 50% of patients now survive 5 years compared to 35% in 2000. However, African American patients may not be enjoying the same health gain as White patients, possibly due to poorer access to healthcare. This study will examine the role of health insurance and living in states with expanded eligibility for Medicaid on treatment patterns and survival in African Americans compared to White patients with multiple myeloma.

Adenylate Kinase 2-A Novel Therapeutic Target in Multiple Myeloma

We identified the adenine nucleotide regulator AK2 as a selective dependency in multiple myeloma (MM) that is more essential for survival of MM cells overexpressing the histone methyltransferase NSD2. Here, we propose a series of experiments to understand the role of AK2 in MM cell fitness and response to existing therapies and elucidate the molecular basis of the increased dependence on AK2 driven by NSD2 overexpression. This study will elucidate the effects of AK2 inhibition in MM and will credential the enzyme as a therapeutic target.

Niclosamide for the Treatment of Relapsed/Refractory Pediatric Acute Myeloid Leukemia

Niclosamide is an FDA approved anti-parasitic drug that is well tolerated and acts synergistically with chemotherapy to kill AML cells. We will conduct a Phase I clinical trial with niclosamide in combination with cytarabine for children with relapsed/refractory pediatric AML. ShRNA/CRISPR screens demonstrated that Bcl-2 is upregulated in niclosamide resistant cells. We will study the effects of the Bcl-2 inhibitor venetoclax in combination with niclosamide in pediatric AML.

Cell-free DNA analysis of persistent CAR T-cell populations in humans

The focus of this research project is to understand how therapeutic chimeric antigen receptor (CAR) T-cells mediate long-term remission of diffuse large B-cell lymphomas. I will use cell free DNA collected from patient plasma to understand if there is an association of CAR T-cell persistence and long-term tumor remission. The goal of this research is to define how CAR T-cells suppress tumors over time to develop better CAR T-cells in the future.

Targeting SYK:ZAP70 coexpression in refractory B-cell malignancies

The B-cell kinase SYK and its T-cell homolog ZAP70 have almost identical functions but are strictly segregated to B- and T-cells. We recently discovered that B-cell malignancies frequently coexpress ZAP70 and that only SYK but not ZAP70 can trigger negative B-cell selection and cell death. Here we test the hypothesis that ZAP70 enables malignant B-cell transformation, test pharmacological SYK-hyperactivation and validate ZAP70 as biomarker of patients who benefit from this approach.

Investigating and targeting the histone acetylation reader protein ENL in acute leukemias

Leukemia often results from aberrant gene expression caused by epigenetic alterations. Previously we discovered a novel histone acetylation reader domain in the ENL protein and demonstrated that this domain is essential for the survival of a wide range of acute leukemias, making it an attractive therapeutic target. We will develop specific inhibitors of ENL activity in acute leukemias and will use mouse models to define the role of ENL mutations identified in patients in leukemogenesis.

Genomic interrogation of high-risk myeloid neoplasms to identify new therapies

The long-term goal of my research program is to improve the outcomes for patients with high-risk myeloid blood cancers, particularly those with loss of chromosome 7 or CUX1. We are tackling this question using an arsenal of innovative methods and tools, including mouse models, human cells and patient samples, and state-of-the-art technologies to examine the cancer cell genome. Accomplishing this work will reveal new treatments and strategies for preventing blood cancers from arising.

Targeting the interplay between signaling and transcriptional dysfunction in myeloid leukemias

Our research program is focused on understanding the intersection between signaling and transcriptional dysfunction in myeloid leukemias. We leverage murine models, cell lines and human samples to uncover how biological context shapes the manifestation of oncogenic programs at the molecular level. Our long-term goal is to harness this knowledge to identify multipronged therapeutic strategies that improve outcomes for patients with myeloid malignancies.

Relevance of ubiquitin dependent proteolysis in Diffuse Large B-cell lymphoma

The goal of this proposal is to investigate the significance of genes of the ubiquitin proteasome system (UPS) that are mutated in Diffuse Large B-cell Lymphoma (DLBCL). Our studies leverage the expertise in the molecular modeling of the UPS in the pathogenesis of DLBCL utilizing mouse models, patient derived xenotransplant (PDX) and cell lines. Our goal is the understanding of how genetic mutations contribute to disease development, progression and therapeutic outcome.

Patient Experience Research and Palliative Care Integration in Malignant Hematology

My research aims to improve the patient and caregiver experience of blood cancer care. To achieve this, I conduct trials of integrated palliative care interventions. Palliative care improves patient and caregiver outcomes for those with solid tumors, but less is known about its role in hematology. My research aims to design and implement integrated palliative care interventions in blood cancer settings, to improve the patient and caregiver experience of illness, regardless of treatment outcome.

Predictors of response to therapy in A051902, a US Intergroup study of duvelisib+CHO(E)P vs CC-486+CHO(E)P vs CHO(E)P in peripheral T-cell lymphoma

We are evaluating if adding duvelisib or azacitidine to standard chemotherapy increases the complete remission rate compared to chemotherapy alone in peripheral T-cell lymphoma. We believe that adding novel agents to chemotherapy will most benefit lymphomas with a T-follicular helper phenotype. We will also study if tests for lymphoma cells in the blood can predict outcomes. We hope these novel therapies will cure more patients and we can identify who is most likely to benefit from them.

Combination Targeted Therapy in Chronic Lymphocytic Leukemia

Targeted therapies have replaced chemoimmunotherapy in chronic lymphocytic leukemia (CLL). We previously reported that combined BTK inhibitor (ibrutinib) and BCL2 antagonist (venetoclax) is highly synergistic. In this proposal, we will conduct a phase II trial of combined non-covalent BTK inhibitor (pirtobrutinib) with venetoclax and obinutuzumab in patients with untreated CLL with primary endpoint of marrow MRD. We will perform BH3 profiling and scRNAseq and correlate with clinical outcomes.

Deciphering the interplay between apoptotic and signaling pathways to target T-lineage acute lymphoblastic leukemia

T-ALL is an aggressive leukemia with limited treatment options. T-ALL cells resist to dying by suppressing their suicide pathways. BH3 mimetics reactivate the suicide mechanisms to induce cell death. We showed that these drugs are effective in T-ALL, but acquired resistance is due to the activation of growth-promoting signaling pathways. The proposed experiments will decipher the relationship between growth and death pathways, identifying unique combination therapies to improve disease outcomes.

Combined targeting of ATR and replicative stress in TP53-mutated AML

This research will test a promising new drug combination in acute myeloid leukemia (AML) carrying TP53 gene mutations, which is resistant to chemotherapy and has a median survival of less than 5 months. Our preliminary data show that TP53-mutated AML is selectively sensitive to the combination of an ATR inhibitor and decitabine. We will confirm activity of this novel drug combination using mouse models of leukemia and human AML samples and explore mechanisms of responsiveness.

Defining PIK3R5-related PI3K gamma dependency as a novel therapeutic target in blood cancers including BPDCN

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive blood cancer without adequate treatment. In a genome-wide CRISPR interference screen, BPDCN was highly dependent on the PI3Kγ pathway and specifically the PIK3R5 adaptor subunit. A subset of leukemias may share this vulnerability. We will interrogate the mechanism of this unique dependency and integrate PIK3R5/PI3Kγ targeting with leukemia therapy. Our goal is to provide novel treatments for PIK3R5-dependent malignancies.

Examining the functional crosstalk between MLL-fusion and MOZ in acute myeloid leukemia

Small molecule inhibitors that target the Menin-MLL-fusion interaction have emerged as therapeutic opportunities for MLL1-r leukemias and are currently in clinical trials. We are now focused on identifying other factors that modulate sensitivity and resistance to Menin inhibition using complementary genomic and biochemical assays. Our goal is to find other druggable dependencies that can further sensitize leukemic cells to this epigenetic therapy and devise more effective treatment strategies.

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 1/2 study of Bexmarilimab, an anti-Clever1 monoclonal antibody, in combination with azacitidine or azacitidine/venetoclax in patients with AML, MDS or CMML

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

Faron (AIM: FARN, First North: 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 1 study in AML (BEXMAB) has been cleared by the FDA and Finnish Medicines Agency is currently enrolling patients.

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.

Novel Combination Immunotherapies for High Risk Hodgkin's Lymphoma

Hodgkin’s Lymphoma (HL) is unique that the tumor cells are surrounded by an inhibitory environment that is able to evade effective anti-tumor responses. Understanding this environment may be a window into effective combination immunotherapies. The goal of this project is to determine if current immunotherapies can change this tumor environment sufficiently to unleash pre-existing anti-tumor T-cell immune responses to allow a more successful incorporation of HL specific cytotoxic T cells.

A novel BAFF CAR-T for treatment of HCL

Despite the success of Chimeric antigen receptor T cell (CAR-T) immunotherapies, disease relapse occurs in a majority of patients. We have developed a novel ligand based BAFF-CAR, that utilizes B cell activating factor (BAFF) as a ligand, which can bind to all three receptors of BAFF, which are expressed by malignant B cells including Hairy Cell Leukemia (HCL). We hypothesize BAFF CAR-T will be an effective therapeutic strategy for HCL.

A phase 1 study of BTX-1188, a dual target protein degrader, in patients with AML or NHL

In November 2010, LLS made an equity investment in BioTheryX originally to support the development of a promising LLS-funded project with Toronto-based University Health Network and is currently supporting "An Open Label, Escalating Multiple Dose Study to Evaluate the Safety, Toxicity, Pharmacokinetics, and Preliminary Activity of BTX-1188 in Subjects With Advanced Malignancies." BioTheryX has a technology platform in the field of targeted protein degradation. This technology utilizes the body's own protein disposal system to selectively degrade and remove disease-causing proteins. It has potential applicability to a very broad range of disease targets, including a wide range of targets that have to date been considered "undruggable." BXT-1188 is an oral, dual target protein degrader specifically engineered to degrade GSPT1 and IKZF1/3. A clinical study of BTX-1188 in patients with relapsed or refractory AML or NHL is currently enrolling.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN): understanding disease biology to improve therapy

We focus on blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive blood cancer with limited treatment options and poor outcomes. We want to understand what causes the disease, develop laboratory tools, and identify new treatments and ways to overcome therapy resistance. We have translated our discoveries to clinical trials. Our goal is to continue this bench to beside approach to develop the next generation of BPDCN therapies that improve survival and minimize treatment toxicity.

Supporting allogeneic CD371 (CLL-1) CAR development for acute myeloid leukemia

In February 2021, LLS made an equity investment in Caribou Biosciences to "Support allogeneic CD371 (CLL-1) CAR development for acute myeloid leukemia." LLS is supporting the preclinical development of CB-012, Caribou’s third allogeneic CAR-T cell therapy, an allogeneic anti-CD371 CAR-T cell therapy for the treatment of relapsed or refractory acute myeloid leukemia (AML). CD371 is expressed on the surface of AML tumor cells and leukemic stem cells, but it is not expressed on normal hematopoietic stem cells, which makes it a compelling target for the treatment of AML. Caribou is applying their genome editing expertise to armor the CB-012 CAR-T product in order to drive persistence and seek maximum patient benefit.

HLA Mutations, GvH Resistance and Relapse Following Allogeneic Hematopoietic Stem Cell Transplant

This project investigates immunogenetic determinants of relapse following allogeneic stem cell transplant for myeloid neoplasia. Herein we will determine molecular modes of inactivation of HLA immunodominant peptide-presentation including HLA mutations, deletion and down modulation as a means of immunoescape. We will also study immunogenetic predictors of the strength of graft vs. leukemia according to the HLA divergence in the context of relapse, TCR repertoire diversity and HLA mutations.

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 2 registration-directed clinical study of ziftomenib (KO-539), a menin inhibitor, in patients with NPM1-mutant relapsed or refractory AML

Starting in July 2010, LLS TAP supported a promising University of Michigan research project led by Jolanta Grembecka, PhD, to develop new treatments for patients with a rare and lethal subtype of leukemia. Through TAP, LLS engaged chemists to improve the properties that produced lead compounds that exhibited potent anti-leukemic activity. In 2014, LLS introduced Kura Oncology to the project that ultimately led to Kura Oncology completing a licensing agreement with the University of Michigan to continue to develop these molecules. Ziftomenib (KO-539) is a potent and selective menin inhibitor that is currently in a Phase 2 registration-directed clinical trial (KOMET-001) in patients with NPM1-mutant relapsed or refractory acute myeloid leukemia (AML).

A phase 1 study of BTX-A51, a multi-kinase inhibitor, in patients with AML or high-risk MDS

In November 2010, LLS made an equity investment in BioTheryX originally to support the development of a promising LLS-funded project with Toronto-based University Health Network and is currently supporting "A First-In-Human, Open-Label, Escalating Multiple-Dose Study to Evaluate the Safety, Toxicity, and Pharmacokinetics of BTX-A51 Capsules in Patients With Relapsed or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome." BTX-A51 appears to block a specific leukemic stem cell target (CK1-alpha) as well as super enhancer targets (CDK7/CDK9) preventing transcription of key oncogenic genes. BTX-A51 has demonstrated preclinical animal efficacy implying the eradication of AML stem cells and the potential for use in multiple malignancies. A clinical study of BTX-A51 in patients with relapsed or refractory AML or high-risk MDS is currently enrolling.

A phase 1 study of KT-413, a dual degrader of IRAK4 and IMiD substrates, in patients with DLBCL

In March 2020, LLS made an equity investment in Kymera Therapeutics to "Support Key Studies with IRAK4 Protein Degraders for Future Development in Hematological Patients." Kymera received this strategic investment from LLS TAP to advance work in an emerging approach to cancer therapy, called “targeted protein degradation.” 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. Kymera received FDA clearance to begin the clinical study and patient enrollment is ongoing.

Supporting CAR-engineered macrophage (CAR-M) development for blood cancers

In February 2021, LLS made an equity investment in Carisma Therapeutics to "Support CAR Macrophage Development for Blood Cancers." Carisma Therapeutics is a spin out company from the University of Pennsylvania (Penn), founded by Saar Gill, M.D., Ph.D. and Michael Klichinsky, PharmD, Ph.D., SVP of Research. Early work at Penn was supported in part by LLS grants. Based on preclinical studies, the company’s highly differentiated CAR-macrophage (CAR-M) platform may have the potential to overcome challenges encountered by other cell therapies such as trafficking limitations to the tumor site, immunosuppressive tumor microenvironments and the heterogeneous expression of tumor-associated antigens. Carisma is working closely with LLS TAP to develop one or more CAR-M therapies for blood cancers.

A phase 2 study of AFM13, a bispecific cell engager targeting CD30 and CD16A, in combination with modified natural killer cells in patients with CD30-positive lymphoma

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 "Bispecific NK Engager AFM13 Combined With NK Cells for Patients With Recurrent of Refractory CD30 Positive Hodgkin or Non-Hodgkin Lymphomas." AFM13 is bispecific tetravalent Innate Cell Engager (ICE®) targeting CD30 on tumor cells and CD16A on NK cells and macrophages. 

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. The company’s proprietary ROCK® platform enables a tumor-targeted approach to recognize and kill a range of hematologic and solid tumors, enabling a broad pipeline of wholly-owned and partnered single agent and combination therapy programs. The ROCK platform predictably generates customized innate cell engager (ICE®) molecules, which use patients’ immune cells to destroy tumor cells.

Supporting in vivo CAR development for blood cancers

In November 2020, LLS made an equity investment in Abintus Bio to "Support in vivo CAR Development for Blood Cancers." Abintus plans to develop a portfolio of first-in-class product candidates that reprogram immune cells in vivo to eliminate tumors utilizing proprietary vectors and vector-engineering technologies to develop an in vivo chimeric antigen receptor (CAR) T platform based on a non-replicating gammaretrovirus. This technology is currently in preclinical testing and could, if successful, support immediate patient dosing, a substantial benefit for patients facing advanced forms of cancer with a poor prognosis. Abintus’ platform is versatile and scalable, so they have the potential to meet the needs of a much larger patient population.

A phase 3 randomized study of magrolimab, an anti-CD47 monoclonal antibody, in combination with azacitidine in treatment-naïve patients with higher risk MDS

In July 2019, LLS expanded its partnership with Forty Seven by making an equity investment to support "ENHANCE: A Randomized, Double-blind, Multicenter Study Comparing Magrolimab in Combination With Azacitidine Versus Azacitidine Plus Placebo in Treatment-naïve Patients With Higher Risk Myelodysplastic Syndrome." LLS funded Stanford University researchers and founders of Forty Seven, Irv Weissman, MD, and Ravi Majeti, MD, PhD, to study seminal work in macrophages. This is a type of immune cell that patrols the body and chews up damaged cells. If a macrophage latches onto a normal cell, a protein known as CD47 sends a “don’t eat me” signal. But lymphoma and leukemia cells are clever and use CD47 to trick the macrophages into ignoring them and letting them grow as cancer. In preclinical mice models, Drs. Weissman and Majeti used an antibody to block the “don’t eat me” signal and stimulate the immune system to recognize the cancer cells as invaders. 

Gilead Sciences acquired Forty Seven in April 2020 and continues to develop magrolimab in multiple clinical studies in patients with myelodysplastic syndrome, acute myeloid leukemia, non-Hodgkin lymphoma, and solid tumors.

A phase 1 study of STRO-001, an anti-CD74 antibody drug conjugate, in patients with advanced B-cell malignancies

In August 2018, LLS partnered with Sutro Biopharma to support "A Phase 1 Open-Label, Safety, Pharmacokinetic and Preliminary Efficacy Study of STRO-001, an Anti-CD74 Antibody Drug Conjugate, in Patients With Advanced B-Cell Malignancies." STRO-001 is a CD74-targeting ADC currently being investigated in a Phase 1 clinical trial of patients with advanced B-cell malignancies, including multiple myeloma and non-Hodgkin lymphoma. STRO-001 is a new generation of ADC with more efficient homogeneous ADC design, which has the potential to minimize unwanted toxicity and improve clinical impact over prior technologies.

Clinical investigation to improve efficacy of CAR-T Cell Therapy for Large B Cell Lymphoma

We are investigating new interventions that could improve the effectiveness of CAR T-cell therapy for lymphoma. A clinical trial will test radiation immediately followed by CAR-T. Larger lymphoma tumors are less likely to respond to CAR-T and we expect that radiation could reduce the amount of tumor, leading to improvement in responses. We will also conduct a series of trials to determine the effectiveness of vaccinations before and after CAR T cell therapy, and if anti-cancer vaccines could improve outcomes.

Cellular Crosstalk In The Normal And Malignant Bone Marrow

We want to understand how leukemia inhibits blood production as this is one of the main causes of death in leukemia patients. We use new microscopy techniques developed by our group to image—for the first time—all types of blood cells and how they are eradicated by leukemia cells. Identification of the mechanisms through which leukemia inhibits blood production will be the foundation for new studies to develop drugs to maintain normal blood levels and prevent death in leukemia patients.

Preclinical Notch inhibition to prevent graft-versus-host disease in mice and non-human primates

We have identified peri-transplant blockade of individual Notch ligands as a new therapeutic strategy to prevent graft-versus-host disease (GVHD) in mice. In a non-human primate model, a single dose of an antibody targeting the Notch ligand DLL4 markedly increased GVHD-free survival as a single agent. Building on the highly conserved role of Notch signaling in GVHD, we propose to identify and characterize the most promising combination therapeutic strategies for clinical translation to patients.

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.

Evolution of megakaryocyte abnormalities in the progression of primary myelofibrosis

My studies are in primary myelofibrosis, a blood cancer characterized by a buildup of fibrous tissue that impairs the bone marrow’s ability to produce normal blood cells. I am studying alterations in large cells in the bone marrow called megakaryocytes and exploring how changes in the bone marrow microenvironment contribute to disease progression. By knowing more about this process, we can uncover new ways to treat the disease before it progresses to a more severe phase.

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.

Improving therapy for CRLF2-rearranged Ph-like acute lymphoblastic leukemia

CRLF2-rearranged ALL is the most common subset of Ph-like ALL, has a very poor prognosis and lacks effective therapy. This project will use two novel approaches to improve treatment. The first is developing proteolysis-targeting chimeras to degrade JAK2 and inhibit constitutive JAK-STAT signaling. In the second approach, we will use CRISPR/Cas9 activating and inhibitory genomic screens to identify cellular dependencies, vulnerabilities and synthetic lethal opportunities for therapy.

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.

PD1 blockade alone and in combination with BTK/ITK inhibition in patients with refractory and recurrent primary central nervous system lymphoma

We study a rare and aggressive brain cancer called primary central nervous system lymphoma (PCNSL). We are using an emerging knowledge of the genetic basis of PCNSL to develop novel clinical trials exploring the use of targeted and immunotherapy agents in PCNSL patients. These trials include assessment of the activity of a PD-1 inhibitor by itself and in combination with a BTK inhibitor in PCNSL patients, as well as identifying any mechanisms of treatment resistance that may develop. The goal of our clinical research is to enhance survival and improve neurologic function in PCNSL patients.

Interventional Epigenetics in Myeloid Malignancies

Myeloid malignancies like acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN) arise due to a combination of genetic mutations and epigenetic abnormalities that sustain the abnormal behavior of cancer cells. The genetic material of the cell is the “hard drive” full of instructions that allow cells to grow, have unique functions, and ultimately live or die. Epigenetics is the “software” of the cell, allowing access to the information from the hard drive in a controlled manner. This interplay between the hardware and the software culminates in gene expression, allowing the genetic material to be read and interpreted. Targeted therapy in other myeloid cancers only works for a fraction of patients. Most myeloid cancers have a constellation of mutations that, in combination, likely determine the outcome of patients. The genetic mutations in myeloid cancers often occur in genes that control the epigenetic regulation of gene expression. While it is not possible to correct the genetic abnormalities in cancer cells, it is becoming possible to target and reverse the epigenetic abnormalities, and either kill the cancer cell or make it behave more normally. The goal of this SCOR is to analyze basic mechanisms of disease in order to arrive at novel therapeutic strategies and develop biomarkers that can predict the likelihood of a therapeutic response.

REACH: Recruitment Expansion through community Access to Clinical trials in Hematologic malignancies

Mayo Clinic Rochester (MCR) is a tertiary center with 35,000 blood cancer visits annually. Circa 70% of patients referred to MCR come from 5 states: MN, WI, IA, SD and ND inhabited by 10,483,946 people living primarily in a rural setting. To improve local care access, MCR has developed the Mayo Clinic Health System (MCHS), a network of 17 community sites of which 7 have oncology care. In 2018, the MCR joined with the University of Minnesota to establish the Minnesota Cancer Clinical Trials Network (MCCTN) that includes 18 sites. These 2 networks encompass large areas of rural, economically disadvantaged populations and unrepresented minorities, including Native Americans, Latinos and African Americans. The MCR is actively supporting clinical research at MCHN sites, including access to clinical trials (CTs) portfolio. Oncology CTs are open in some of MCHS sites but of the 25 currently open, only 2 CTs target blood cancers. The University of Iowa/Mayo Clinic Lymphoma SPORE has opened epidemiological trials in the MCHS. The MCCTN is new and none of the 3 open CTs are hematologic. Lymphoma study accruals from the MCHS include 42 patients (1 therapeutic; 41 lymphoma epidemiology). The robust epidemiology trial accrual demonstrates that these new lymphoma patients are being seen at these sites and are willing to consent. While many patients from rural communities are seen at MCR for initial diagnosis, these patients often are unable to enroll into trials due to distance from MCR. Feedback from providers from both Networks identified barriers to accrual to lymphoma CTs: i) lack of local lymphoma trials; ii) competition with the more common solid tumor CTs for scarce resources; iii) very busy clinical practices that limits dedicated time for enrollment of intensive complex hematology patients. The practice pressure particularly affects patients requiring language or financial assistance. In this proposal, we outline our plans to address the 3 barriers identified.

Molecular regulation of PD-L1 expression and anti-tumor immunity in diffuse large B cell lymphoma

Copy gains of the chromosomal region (9p24.1) containing the PD-1 ligands, PD-L1 and PD-L2, are a recurring genomic alteration in DLBCL, and we have found that the presence of PD-L1 gene alterations are a genetic biomarker of DLBCLs that harbor a T cell-inflamed phenotype.

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.

Understanding SARS-Cov-2 evolution in haemato-oncology patients

Through phenotypic and functional studies of immune cells, proteomic mapping of immune responses and genomic studies of variant strains, this project will assess the evolution of natural SARS-CoV-2 infection and COVID-19 vaccine responses in hemato-oncology patients. Integration of immunological profiles and genomic outcomes with clinical characteristics will inform future best patient management, especially for those patients at risk of prolonged infection with long term viral shedding.

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.

Identification of therapeutic targets sensitizing acute myeloid leukemia to BCL2 inhibitors

Venetoclax is a medication that can induce cell death of acute myeloid leukemia (AML), but its effectiveness needs to be further improved to benefit more patients. We are conducting a functional genetic screen to identify cooperating targets that enhance the efficacy of venetoclax and investigate the underlying molecular mechanism. Our study will provide valuable insights for understanding cell death regulation in AML and facilitating the clinical application of venetoclax for AML treatment.

Unraveling the mechanisms of immune checkpoint dysfunction in cutaneous T cell lymphoma

Cutaneous T-cell lymphoma (CTCL) is a disfiguring, incurable malignancy profoundly affecting patients’ appearances, quality of life, and relationships. Standard treatments only benefit 30% of patients with limited duration. Rather than focusing on the tumor alone, we target the adjacent tumor microenvironment, which nourishes tumor growth. We have begun a clinical trial of durvalumab, which is an inhibitor of the checkpoint protein receptor PD-L1. We are currently investigating how immune checkpoint proteins together with the immune booster lenalidomide affect CTCL growth. This research will benefit not only those with CTCL but many other cancers.

The impact of telomere maintenance on intestinal mucosal injury and regeneration during allogeneic stem cell transplantation for myeloid malignancies.

Short telomeres, the protective caps at the ends of DNA, are associated with increased risk of fatal toxicity among stem cell transplant recipients. We will determine 1) the relationship between recipient telomere length and intestinal injury after transplant and 2) how telomere length influences intestinal healing in a transplant mouse model. The goal of this work is to identify transplant patients at increased risk of toxicity and design therapies to improve patient survival.

The role of Plek2 in the pathogenesis of myeloproliferative neoplasms

Our research focuses on the study of a novel therapeutic target, named Plek2, in the development of myeloproliferative neoplasms (MPNs). MPNs can progress to leukemia and there are currently no cures. We use animal models and patient samples to study how elevated levels of Plek2 causes the disease and identify approaches to suppress the function of Plek2. Our goal is to use the knowledge from this study to develop novel therapies to treat MPNs.

CAR T-cell therapy in central nervous system (CNS) lymphoma: a study in safety and efficacy and a model in which to study mechanisms of neurotoxicity

CAR T-cells are highly effective in lymphoma but limited by a profound and potentially fatal toxicity involving the central nervous system (CNS). Little is known about how CAR T-cells eliminate lymphoma cells in the CNS nor how this therapy causes toxicity. I will study CAR T-cells in patients with CNS lymphomas with the goal of expanding CAR T-cell indications. I will also examine serial blood and CNS samples to understand neurologic toxicity to inform new therapies to control this toxicity.

Targeting mitophagy of leukemia stem cells for therapy

Enhancing the commitment of leukemia stem cells (LSCs) is a promising therapeutic strategy against blood cancer, but tracking the division pattern of individual cells has proved difficult. We have established a novel technical regimen to assess the behavior of individual LSCs and their cell fate in vivo. Genetic mouse models and mouse models engrafted with leukemia patient samples are also used. Our project seeks to elucidate the role of mitophagy in the control of LSC division balance, which may facilitate new therapy targeting these cells.

Cytokine induced memory-like NK cell immunotherapy to target post transplant relapse

Coming soon.

Treatment tailoring by optimized early residual disease assessment in classic Hodgkin lymphoma

Incorporation of circulating tumor DNA (ctDNA) monitoring into clinical trials of classic Hodgkin lymphoma (cHL), which is the primary objective of this proposal, will allow to: i) precisely define ctDNA accuracy in anticipating disease course; and ii) test if ctDNA results can be used to guide treatment decisions. The project results can translate ctDNA monitoring as a routine response assessment tool for cHL.

Niclosamide for the treatment of relapsed pediatric acute myeloid leukemia

Niclosamide is an FDA approved anti-parasitic drug that is well tolerated in adults and children. AML cells are sensitive to niclosamide, act synergistically with chemotherapy in vitro, and inhibit the proliferation of primary AML stem cells in vivo. We propose to examine the effects of niclosamide in combination with chemotherapy in animal models of AML and study the mechanism of action of niclosamide in AML cells in anticipation of a clinical trial in children with relapsed AML.

Reaching out to underserved & minority patients with hematological diseases in the southeastern US

Vanderbilt-Ingram Cancer Center (VICC) is the only NCI designated cancer center that serves both adult and pediatric populations in TN, one of the highest cancer-mortality states in the country. In fact, TN rural dwellers encompass about 30-50% of the states’ population, many with lower per-capita income and high school graduation rates. Influencing cancer care by facilitating underserved and minority populations to access therapeutic clinical trials as well as those focused on screening and prevention strategies remains a cornerstone objective. The Vanderbilt Health Affiliated Network (VHAN) serves as the largest provider for an organized network of hospitals, clinics, and health systems across TN. This network encompasses 12 health systems and 61 hospitals. Within VHAN, the VICC has had a formal affiliation with Baptist Memorial Healthcare Corporation (BMHCC) since 2012. BMHCC is affiliated with 22 hospitals and provides care for 8000 new cancer patients (pts) annually covering 111 counties totaling 4.3 million people. This includes 44% of the 252 counties and parishes in the Delta Regional Authority, congressionally acknowledged as the most indigent population in the US. The primary objective of the VICC community center affiliation with BMHCC is to enhance the regional level of cancer care and to advance cancer research efforts. VICC has provided guidance on a regular basis to assist BMHCC in the establishment and implementation of the Minority and Underserved National Cancer Institute Community Oncology Research Program (NCORP) grant as a successful and sustainable program. BMHCC has become amongst the top recruitment sites for NCORP, with steady growth in the proportion of rural pts seen across the health system. VICC continues to be a resource for BMHCC on providing consultations, training, and best practices for specialized services such as clinical research, radiation oncology, cancer screening, stem cell transplantation and community engagement.

Exploiting metabolic dependencies, tumor plasticity and their consequences for drug response of HCL

We have long standing experience in the field of HCL research. The aim of this research proposal is to characterize HCL on single cell level across multiple layers to uncover interactions of HCL with its microenvironment, which supports HCL cell survival. We will further explore metabolic and functional dependencies of primary HCL cells, and we hypothesize that their attenuation compromises HCL cell survival. Finally, we aim to pharmacologically disrupt these pro-survival pathways in HCL cells.

Co-targeting BET bromodomain proteins and aberrant Ras signaling in pediatric AML

We will test rational drug combinations in accurate preclinical model systems that reflect the distinct genomic features of pediatric AML. The use of genetically accurate mouse models to inform clinical translation is particularly important in pediatric AML given its relatively low incidence and difficulties inherent in testing drug combinations in children. Our preliminary studies have identified combined BET and MEK inhibition as a particularly promising combination for pediatric AML.

Safety and efficacy of booster doses of BNT162b2 vaccine in immunocompromised patients with a cancer diagnosis

It is now well-established that COVID-19 in patients with cancer carries a higher morbidity and mortality, especially in patients with hematologic malignancies (Kuderer et al, Lee et al). Effective vaccines have been developed and authorized by the FDA to combat this pandemic (Pfizer NEJM, Moderna NEJM, J&J NEJM). However, emerging data suggests that despite these vaccines inducing high levels of immunity in the general population, patients with hematologic malignancies have lower rates of seroconversion for the SARS-CoV-2 Spike antibody (Thakkar et al Cancer cell, Dimpy Shah cancer cell, Sheeba Irshad cancer cell). Evidence has also suggested that specific therapies, such as anti-CD20 antibodies, BTK-inhibitors and stem cell transplantation have an association with lower rates of seroconversion (Thakkar et al Cancer cell, Thakkar et al Nature cancer, Herishanu at al blood 2021). Novel immunization strategies such as booster dosing are urgently needed to protect this high-risk patient population. We propose a study to administer a third dose of the BNT162b2 mRNA vaccine to patients with cancer who have a negative SARS-CoV-2 Spike IgG at least 14 days after 2 doses of the BNT162b2 vaccine

ASH1L degradation as a new treatment for acute leukemia

This project is focused to develop small molecule degraders of ASH1L histone methyltransferase as a treatment for aggressive sub-types of AML and ALL with high expression of HOXA genes by utilizing the PROTAC (proteolysis targeting chimera) approach. Optimization of ASH1L degraders and their comprehensive evaluation in in vitro and in vivo leukemia models are proposed. We expect these studies will lead to new therapeutics for aggressive acute leukemias with high HOXA expression.

Targeting mitochondrial dynamics in venetoclax-resistant acute myeloid leukemia

Although new targeted therapies have been discovered and approved for the treatment of various types of leukemia, in many cases patients do not respond or develop resistance to treatments. My LLS-funded studies shed light on the mitochondria adaptations which enable cancer cells escape cell death induced by the treatments, while suggesting novel therapeutic strategies.

Enhancing CAR T cell therapy for multiple myeloma

My overall focus is to improve CAR T cell therapy for multiple myeloma. Our clinical trial uses CAR T cells targeting BCMA as first line therapy for high-risk multiple myeloma to assess whether early use of CAR T cells is safer and more effective than use in patients with relapsed disease. Half of patients will also receive CAR T cells targeting CD19 to assess whether this can improve the duration of response to anti-BCMA CAR T cells. Our goal is to evaluate whether early use of CAR T cells is a safer and more effective way to use CAR T cells for multiple myeloma patients.

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.

Optimizing ibrutinib combination strategies to achieve minimal residual disease negativity in CLL

We seek to optimize combination therapy for chronic lymphocytic leukemia with ibrutinib. We will address this question through 2 clinical trials combining ibrutinib with chemoimmunotherapy or an antibody. We will also examine the biology of CLL cells at a genetic and functional level to predict who will have the best response to therapy and to identify resistance mechanisms. Our goal is to develop curative combinations for CLL and to understand resistance in the patients who are not cured.

Overcoming ibrutinib resistance in mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive blood cancer which affects about 3,000 individuals in the United States annually. Despite advances of novel therapies in blood cancers, MCL remains incurable, and patients ultimately succumb to disease. We seek to evaluate longitudinal samples from patients with MCL treated with novel therapies to understand the mechanisms of drug resistance. We identify novel targets, with a particular focus on protein turnover pathways, to overcome drug resistance and improve survival of patients with MCL.

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.

Discovery and characterization of an immunosuppressive tumor microenvironmental (TME) niche in classic Hodgkin lymphoma

Dr. Shipp and her colleague, Scott J. Rodig, MD, Ph.D., are mapping the immune microenvironment in classical Hodgkin lymphoma.

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.

Deciphering immune cell heterogeneity and transcriptomic changes associated with CRS development and severity in CAR-T cell treated patients

We seek to understand the mechanisms of Cytokine Release Syndrome (CRS), the most common and potentially life-threatening toxicity associated with CAR-T cell therapies. We are using cutting-edge approaches to determine the cascade of events leading to the development of CRS and therefore define new candidates for CRS prevention and/or resolution. We will describe a cellular and molecular atlas associated with CRS development and severity, thus providing more specific and reliable candidates for therapeutic targeting. These findings may inform strategies to prevent CRS of cancer patients receiving CAR-T therapies.

The biological and therapeutic consequences of SF3B1 mutations in myelodysplastic syndromes

My lab studies how common mutations affecting RNA splicing, a critical step during expression of most human genes, give rise to myelodysplastic syndromes, leukemias, and other malignancies. We combine experimental and computational studies to create new models of these disorders and thereby understand their molecular origins. In the long term, our goal is to identify new therapies for treating these disorders, which currently have limited treatment options.

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.

Towards a rational targeted therapy for Waldenstrom's Macroglobulinemia by kinome-centered loss-of-adhesion and synthetic lethality screens

We have previously demonstrated that disrupted retention of the malignant B cells within lymphoid organs is a key mechanism of action of the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, underlying its unprecedented high clinical efficacy in the treatment of chronic lymphocytic leukemia, mantle cell lymphoma and Waldenström’s Macroglobulinemia (WM). Unfortunately, apart from innate (primary) resistance, a significant subset of patients who receive prolonged treatment with ibrutinib develop (secondary) therapy resistance. Considering microenvironment-dependence as the Achilles’ heel of WM cells, we hypothesize that induction of homelessness by targeting localization (homing and retention) as well as survival/proliferation of WM cells in their lymphoid organ microenvironment by combination therapy may overcome innate (primary) resistance and prevent acquired (secondary) drug-resistance, providing a powerful strategy to cure WM. Therefore, our aims are: 1) to identify the signaling pathways and kinases (given their druggability) that control WM cell retention and outgrowth; 2) to identify kinases whose inhibition sensitizes WM cells to the anti-adhesive and growth-inhibitory effects of ibrutinib, and 3) to explore and exploit their potential as therapeutic targets for development of novel targeted (combination) therapy for WM patients.

Advancing New Therapeutic Strategies for Pediatric Acute Leukemias

Dr. Kimberly Stegmaier is performing pre-clinical research to identify promising therapeutic strategies for pediatric leukemia. Pediatric blood cancers comprise about 40% of all pediatric cancers. The most common pediatric blood cancer is acute lymphoblastic leukemia (ALL), which is curable in most patients through the use of chemotherapy. Though beneficial in the short term, destroying the cancer through chemotherapy often leads to long term health problems. For those that do not respond to chemotherapy, there are fewer therapeutic options. Another pediatric blood cancer is acute myeloid leukemia (AML), which is a more aggressive and lethal disease. Therefore, many pediatric acute leukemia patients require better therapeutic options, and a precision medicine approach targeting specific mutations will likely lead to a better clinical benefit.

Development of natural killer (NK) cell-based therapies to treat MYC-high pediatric lymphoid cancers

Refractory pediatric B- and T- lymphoid cancers exhibit hyperactivation of MYC and its downstream pathways. Experimentally, MYC inactivation sustains tumor regression. However, MYC’s requirement in normal B/T-cells has hampered the development of MYC inhibitors. Recently, we showed that MYC-High B/T-Lymphoid Neoplasms (B/T-MLN) evade Natural Killer (NK) cell surveillance. Hence, we propose to develop targeted off-the-shelf NK therapies as an alternative to MYC inhibition for treating B/T-MLN.

Pharmacological inhibition of the transcription factor PU.1 as a novel treatment for acute myeloid leukemia

Transcription factors are components of a cell which control our genetic information and are known to have altered function in diseases such as Acute Myeloid Leukemia (AML). I am investigating how we can better understand and use novel transcription factor drugs as therapy for AML. This involves using CLICK-chemistry drug localization studies and creating transcription factor occupancy maps of the genome. Overall, my work will help to understand the inner workings of transcription factors in disease and provide a new therapeutic option for the treatment of AML.

Discovery of Aging-Driven Mechanisms Causing Clonal Hematopoiesis (CH) and its Progression to Hematological Malignancy

My research focuses on why and how risk of acute myeloid leukemia (AML) increases with aging. Studying naturally aged mouse models in combination with mice engineered to express mutations commonly found in human blood stem cells with aging, we are investigating whether certain inflammatory factors that increase during aging increase the risk of leukemia. My goal is to identify biomarkers to assess risk of AML development in aging individuals and define new therapeutic targets to prevent AML.

Beyond azacitidine: investigating new therapeutic strategies for the treatment of MDS

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.

Precision targeting of BFL-1 and MCL-1 in pediatric leukemias to overcome treatment resistance

Pediatric leukemia cells hijack the BCL-2 family signaling network to overexpress a range of anti-apoptotic proteins, including BFL-1 and MCL-1, and thereby enforce cellular immortality and cause treatment resistance. Here, we will harness novel and unique stapled peptides with the capacity to selectively target BFL-1, MCL-1, and importantly, both targets simultaneously, in order to reactivate the cell death pathway in MCL-1 and BFL-1 dependent pediatric leukemias.

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.

Selective BRD4 degradation in pediatric leukemia

There exists compelling rationale for targeting BRD4 therapeutically in acute leukemia yet currently available inhibitors lack selectivity and demonstrate toxicity. We have developed a selective degrader molecule that can specifically bind and degrade BRD4. Here we propose to chemically optimize our BRD4-degrader and evaluate its mechanisms and anti-cancer effects in models of leukemia to determine if it is a novel therapeutic for the treatment of pediatric acute leukemia.

Functional and mechanistic roles of BCAA metabolism in the progression of myeloproliferative neoplasms

The processes that control the progression of myeloproliferative neoplasms to leukemic transformation remain largely unknown. We have developed genetic mouse models that recapitulate leukemia progression in humans. We aim to discover new regulators and pathways controlling the propagation of leukemia stem cells as targetable vulnerabilities. Our study promises to provide critical insights into developing new and generalizable therapies to selectively eliminate leukemia stem cells.

Checkpoint-Based Immunotherapy in Follicular Lymphoma

This project focuses on designing new immunotherapy approaches for the treatment of patients with follicular lymphoma. It is based on a clincal trial that tests combinations of antibodies, with the goal of making the patients’ own immune systems more effective at attacking their lymphoma. Through analysis of tumor and blood samples from the patients on the trial, we hope to gain a deeper understanding of the biology of follicular lymphoma and its vulnerability to immune attack, which will help to design the next generation of trials. The trial and sample collection are currently ongoing.

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.

Targeting the stress response machinery in pediatric T cell acute lymphoblastic leukemia (T-ALL)

Current intensive chemotherapy regimens to T cell acute lymphoblastic leukemia (T-ALL) patients come at the cost of serious side effects while a significant percentage of patients experience relapse. We have recently demonstrated that T-ALL is addicted to the function of a stress response pathway activated in the presence of proteotoxic stress. Here, we present a novel approach to exploit the altered dependency of T-ALL on stress responses and target leukemia-specific vulnerabilities.