Research We Fund

Targeting the microenvironment to increase immunity and immunotherapy response in DLBCL

To survive and proliferate lymphoma cells must co-opt normal cells residing the tumor microenvironment. This process results in the suppression of the activity of immune cells that otherwise will attack cancer cells. In this project we will develop a novel oral treatment that by acting on the microenvironment will restore lymphoma immunity and increase the activity of immunotherapy.

Exploiting escape from Y-inactivation as a synthetic dependency in MYC-driven lymphoma

As a lymphoma develops it expresses genes that are normally silenced to convey a survival advantage. When these genes are on the X or Y (sex chromosomes) they may present a gender-specific therapeutic target. We have identified a gene (DDX3X in females or DDX3Y in males) that is reactivated in lymphomas such that the lymphomas cannot survive if this gene is removed. This project will develop new ways to inhibit DDX3X and Y as a novel treatment for poor-risk and aggressive lymphoma.

Targeting TP53-Y220C mutant AML

TP53-Y220C is a recurrent hotspot TP53 mutation observed predominantly in AML and MDS among hematological malignancies. This study aims to investigate the mechanism of action and therapeutic activity of PC14586, a compound designed to bind p53-Y220C protein and stabilize it in the wild-type conformation and to develop mechanism-based combinations that improve its efficacy in TP53-Y220C mutant AML.

Pluripotent Stem Cell-derived CAR-T and CAR-NK Cells for Immunotherapy of Leukemia and Lymphoma

Cytotoxic cells of the immune system, including T and NK cells, can be targeted to seek out and destroy leukemia, lymphoma and myeloma cells by engineering them to express chimeric antigen receptors (CARs) which empower the cell to home to and kill the cancer cells. Typically, such CAR-T and CAR-NK cells are generated from a patient's own blood, but sometimes heavy pre-treatment with chemotherapy leaves inadequate supplies of T and NK cells. We propose to generate T and NK cells from Pluripotent Stem Cells, which through genetic manipulation can be rendered suitable for treating any patient with an "off-the-shelf" cell product, hence facilitating otherwise cumbersome, labor-intensive, and expensive patient-specific cell therapies.

Improving outcomes of multiple myeloma using TGF-beta resistant BCMA-targeted CAR T cells

Immunotherapy using chimeric antigen receptor (CAR) T cells, or CARTs for short, holds great promise for improving outcomes and survival of patients with relapsed and/or refractory multiple myeloma (RRMM). Next-generation “armored” CARTs that can overcome transforming growth factor beta (TGF-beta) dependent immune suppression in the tumor microenvironment may provide deeper and more durable disease control than the TGF-beta sensitive CART products currently in clinical use.

Enhancing the “fitness” of anti-BCMA CAR T cells for improved efficacy in multiple myeloma

Chimeric antigen receptor (CAR) T cell therapy is a form of immune-based therapy where a patient’s own immune cells are genetically engineered to recognize and kill the tumor cells. This therapy has revolutionized the treatment of certain blood cancers and excitingly, two CAR T cell products were recently approved for the treatment of multiple myeloma.

Despite impressive initial clinical data showing responses in 73-98% of patients, most patients still relapse after CAR-T cell therapy within 3 years. Therefore, there is a significant unmet need to further enhance the effectiveness of CAR T cell therapy in this disease. In this project we will investigate whether an approach we have shown to make CAR T cells “fitter” and more effective in solid tumors is also effective in the context of multiple myeloma.

Next-Generation Targeted Therapy in Mantle Cell Lymphoma and Transformed Follicular Lymphoma

The field of cancer treatment has made remarkable progress with the adoption of targeted therapy; however, small molecule drugs have limitations such as drug resistance and off-target toxicities. To overcome these challenges, we have developed an innovative approach that enhances the potency and precision of small molecule drugs. Our cutting-edge high-precision pretargeted nanoparticles can deliver potent triple inhibitors that effectively combat drug-resistant mantle cell lymphoma and dual proteolysis targeting chimeras (PROTACs) for treatment of transformed follicular lymphoma. Our proposal is supported by extensive preliminary data, and we are excited to be at the forefront of this revolutionary novel treatment strategy.

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

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

Stem cell features and Notch signaling in p53 deleted multiple myeloma

We have investigated the consequences of p53 loss on stem cell properties, namely clonogenic growth, self-renewal, and drug resistance in multiple myeloma. We have found that both the level of Notch signaling and BCMA impact these properties, and we will explore novel strategies to improve outcomes in p53 mutant multiple myeloma.

Arming NK Cells to Target B7-H3+ AML Cells

In order to develop a novel immunotherapy approach to treating AML, we propose targeting B7-H3 (CD276), a promising immune checkpoint that has been reported to inhibit NK cell activation. We have generated a novel anti–B7-H3 monoclonal antibody (T-1A5) to block B7-H3 function, showing the best in vitro and in vivo activity against AML cells. We will test the hypothesis that combination strategies such as targeting B7-H3 along with BCL2 inhibition (venetoclax) or IL-15r agonist (NKTR-255) result in synergistic inhibition of AML growth.

Understanding molecular determinants of immune evasion to CAR-T cells at single clone resolution

Cellular immunotherapies such CAR-T cells are now firmly established as major pillars of anti-cancer therapy particularly in B-cell malignancies. However, despite their remarkable success in mediating an objective clinical response in up to 90% of patients, long-term durable remissions remain confined to only a minority of patients. It is now increasingly apparent that genetic evolution through the acquisition of new mutations cannot solely explain the molecular basis for therapeutic resistance. Therefore, to meet our ambition of precision medicine we need a better understanding of both the genetic and non-genetic mechanisms of malignant clonal dominance and therapeutic adaptation. To address this important challenge, we have developed new ex vivo and in vivo (mouse models) of resistance to CAR-T therapy. These will be coupled to a synthetic clone tracing strategy termed SPLINTR (Single-cell Profiling and LINeage Tracing) using expressed barcodes. In this proposal we will use SPLINTR in our models to uncover the clone intrinsic properties of cancer cells that enable them to evade these pioneering cellular immunotherapies. This research will deliver a blueprint around which future clinical trial strategies could be enabled to improve outcomes with these ground-breaking therapies.

Inhibition of PKCβ as a strategy for BTK inhibitor refractory CLL

Patients with CLL that have progressed on BTK inhibitors have high risk disease with few clinical options. Here we propose a novel, selective inhibitor of PKCβ, MS-553, as a strategy for these patients. Our project will evaluate this drug alone and in combination with venetoclax preclinically and will perform correlative studies from an ongoing phase 1/2 trial of this drug alone and in combination with venetoclax.

Discovery and therapeutic targeting of novel mechanisms driving Double Hit Lymphomas

Double-hit lymphoma (DHL) is an aggressive form of diffuse large B-cell lymphoma (DLBCL) defined by co-occuring MYC and BCL2 rearrangements. DHL has been linked to very poor outcomes when treated with R-CHOP chemotherapy. Effective treatments to prevent treatment failure remain a critical unmet need. This proposal will develop novel, mechanism-based therapeutic regimens for DHL that overcome chemotherapy resistance and defective immune surveillance to improve outcomes.

Developing Novel CAR-T Cell Therapy For Hematologic Malignancies

We observed that patients with many hematologic cancers expressed high levels of DKK1 and generated novel human DKK1-A2 CAR-T cells that can kill cancer cells from HLA-A2+ patients with myeloma, lymphoma, or leukemia. We also found that Th9-polarized T cells have enhanced antitumor effects in vivo. In this proposal, we will determine 1) whether and how Th9-polarized DKK1-A2 CAR-T cells are promising effector T cells for immunotherapy of human patients, and 2) whether Th9-polarized DKK1-A2 CAR-T cells are associated with reduced on- and off-target toxicities. Completing these studies are critical for developing new and effective CAR-T therapy for patients with hematologic malignancies who are still dying from the disease.

Developing selective inhibitors of the b-catenin/BCL9 transcriptional complex for myeloma therapy

The b-catenin/BCL9 transcriptional complex, is a novel dependency in multiple myeloma (MM). Disruption of this complex inhibits MM cell growth in culture and in MM xenograft models. Development of potent selective b-catenin/BCL9 inhibitors will provide valuable tools to further investigate their mechanism of MM inhibition. We have established a chemistry, structural biology, and molecular pathology platform to facilitate novel inhibitor development, and explore its translational potential in MM.

Designed biosensor to enhance CAR T cell therapy for multiple myeloma

We will develop a novel T cell therapy strategy for multiple myeloma (MM) that will combine existing chimeric antigen receptors (CARs) with a novel designed biosensor responding to soluble factors abundantly present in the MM bone marrow environment in patients. The biosensor will be expressed as novel type of chimeric receptor in T cells concomitantly with the CAR and signal the T cells to persist longer and keep eliminating cancer cells from the body. We will deeply characterize the effects of our novel biosensor in CAR T cells to precisely understand how the treatment works. If successful, we expect that CAR T cell therapy for MM can be made more efficient, and the same strategy could potentially also be applied to other cancer types.

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

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

Towards clinical testing of epitope editing to enable novel adoptive immunotherapies

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

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

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

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

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

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.

Optimizing MICA/B antibody for AML by selective binding to Fc activating receptors

Acute myeloid leukemia (AML) is a blood cancer characterized by poor clinical outcomes. We developed an antibody that inhibits AML in models by triggering anti-leukemia immunity. Now we developed a new version of this antibody with higher affinity to the leukocyte receptors that mediate anti-leukemia immunity. We will establish the ability of this optimized antibody to elicit greater inhibition of AML. The studies will generate important information about how to induce anti-leukemia immunity.

Anti-Sox2 immunotherapy to prevent multiple myeloma relapse

Advances in multiple myeloma (MM) therapy have improved survival, but serial cycles of response and relapse still lead to treatment-refractory and fatal disease in nearly all patients. To specifically target mechanisms of MM relapse, we propose to develop an immunotherapy targeting Sox2, a stem-cell transcription factor implicated in clonogenic MM growth that enables relapse.

A Polyomic Approach to Chronic Graft-versus-Host Disease (cGvHD) Biomarkers in Adults

Our team is the first to develop a polyomic pediatric cGvHD biomarker test for assessing the risk of developing cGvHD. A cooperative adult phase III clinical trial, CTTC1901, between Canada and Australia, focused on decreasing cGvHD (N=350 patients), offers an ideal opportunity to validate adult cGvHD biomarkers. This proposal will utilize the pediatric polyomic approach to validate a cGvHD risk assignment and diagnostic algorithm in adult hematopoietic stem cell transplant (HSCT).

Dissecting the biology and exploiting the dependency of myeloma cells on P300/CBP

In recent work of our collaborating labs, the protein acetyltransferases P300 and CBP emerged as potent and preferential dependencies for multiple myeloma (MM) based on genetic depletion, catalytic inhibition or chemical degradation studies. Our current project will define distinct vs. redundant molecular and biological functions of P300/CBP in MM, identify the mechanisms of resistance to their inhibition/degradation and exploit these findings to develop new therapeutic modalities to treat MM.

Immunotherapeutic Targeting of FCRL1 in CLL

Evolving insights into the B cell-restricted FCRL1 surface protein reveal that it integrates with critical signaling pathways and is a promising immunotherapeutic target in CLL. Based on preclinical evaluation of novel FCRL1 monoclonal antibodies, we propose developing chimeric antigen receptor (CAR) T cells for targeting in unique mouse models and patient-derived cells. The results will form the basis for strategic drug development and clinical testing in CLL and related B cell malignancies.

Identification and Molecular Analysis of Pre-Myelofibrotic Stem Cells

Myelofibrosis is a severe myeloproliferative neoplasm with no known cure.We have obtained unique insights into the underlying mechanisms responsible for the emergence of myelofibrosis and designed new approaches to selectively control it. By combining our mutation-specific isolation methods with single cell sequencing, we will identify myelofibrosis-initiating stem cell populations, demonstrate efficacy of stem cell targeting and enumerate residual normal stem cells to inform a Phase I/II trial.

Impact of sublethal radiation dose on tumor response, microenvironment and the immune system

Extremely low dose radiation can improve blood cancer outcomes. But the mechanisms of how sublethal radiation (SRT) affects tumors, the microenvironment and immune system remain unclear. We envision a broad, nuanced role for SRT with benefits across diverse clinical situations and propose 3 clinical trials with deep translational components. Each can be paradigm-changing, but are thematically unified to improve mechanistic understanding of how such exceptionally small doses might offer so much.

Peripheral blood-based disease monitoring by mass spectrometry in patients with multiple myeloma

The present project will investigate the ability of quantitative immune precipitation mass spectrometry (QIP-MS) to anticipate relapsed or progressive disease in peripheral blood samples from patients with multiple myeloma. In the context of the GEM2014MAIN trial (lenalidomide and dexamethasone plus or minus ixazomib as maintenance), we will assess the presence of disease by QIP-MS in parallel with conventional methods in serum and next generation flow in bone marrow samples.

Targeting Siglec15 to promote immune response to malignant B cells

The goal of this project is to explore a novel immunologic therapeutic target for hematologic malignancies, SIGLEC15 (Sig15). The central hypothesis is that Sig15 is aberrantly expressed in malignant B cells, is released to attenuate immune responses and can be targeted therapeutically to promote immune responses to malignant hematopoietic cells. This work will accelerate therapeutic exploitation of the immune system for the treatment of leukemia and lymphoma by targeting Sig15.

Development of therapeutic strategy for the treatment of MDS

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

Systematic multiomic profiling of tumor and immune cells for non invasive detection of early myeloma

Multiple myeloma remains largely incurable and there is consensus that the pathway to cure cancer involves treating patients earlier. Thus, there is an unmet need to develop methods for early detection of pre-malignant disease and to help tailoring treatment for patients with smoldering myeloma. We aim to develop new methods for minimally invasive characterization of patients with smoldering myeloma in order to treat disease causation instead of symptomatology and increase curability rates.

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.

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.

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.

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.

T cells with native and chimeric receptors against multiple tumor targets for acute myeloid leukemia

Adoptive T cell therapies for acute myeloid leukemia face numerous hurdles such as limited target antigens, immunosuppressive tumor environment as well as the loss of efficacy due to downregulation of the targeted antigen. The goal of our project is to address some of these challenges with a single T cell product targeting multiple tumor associated antigens that have limited expression on healthy tissues via a novel combination of native T cell receptor and gene engineered CAR targeting.

Restoring lymphoma immunosurveillance by combined EZH2 inhibition and immunotherapy

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