Research we fund

While many patients with diffuse large B cell lymphoma (DLBCL) are cured with initial treatment, some patients relapse even after multiple therapies, and their outcomes are poor; we believe that the quality of the patient’s T cell memory plays a critical role in determining how they respond to treatment. To investigate, we will analyze the response pattern of circulating immune cells in cured and relapsed DLBCL patients, as well as the immune signals generated by the tumors, and create CAR T cells from the T cells with anti-tumor properties found in cured patients. We will evaluate the ability of these CAR T cells to fight lymphoma; if successful, our research can rapidly be translated into new immune therapies for patients with high risk or relapsed DLBCL.

Project Term: July 1, 2024 - June 30, 2027

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.

Project Term: July 1, 2024 - June 30, 2027

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.

Project Term: July 1, 2024 - June 30, 2027

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.

Project Term: July 1, 2024 - June 30, 2027

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.

Project Term: July 1, 2024 - June 30, 2027

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.

Project Term: July 1, 2023 - June 30, 2026

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

Project Term: July 1, 2023 - June 30, 2026

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.

Project Term: July 1, 2023 - June 30, 2026

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

Project Term: July 1, 2023 - June 30, 2026

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.

Project Term: July 1, 2023 - June 1, 2026

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

Project Term: July 1, 2023 - June 30, 2026

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.

Project Term: July 1, 2023 - June 30, 2026