Research we fund

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

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.

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

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

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.

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.

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).

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.

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.

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.