Research we fund

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.

Project Term: September 1, 2023 - August 31, 2026

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

Project Term: June 1, 2023 - May 31, 2026

This project will evaluate the association of insurance type with insurer rejection and patient abandonment of new OAM prescriptions for blood cancers, overall and by sociodemographic factors. It will also evaluate the association of cost sharing with patient abandonment of OAM prescriptions for blood cancers and conduct simulations under alternative cost sharing scenarios to inform policy reform proposals among commercially insured enrollees. Finally, the study will evaluate the effect of cost-sharing reductions under the Inflation Reduction Act on patient abandonment of new OAM prescriptions for blood cancers among Medicare Part D enrollees, overall and by sociodemographic factors.

Project Term: June 1, 2023 - May 31, 2026

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

Project Term: June 1, 2023 - May 31, 2026

Our study is designed to directly inform the pathways through which health insurance influences access to care at an SCC for individuals with AYA ALL using a combination of cancer registry, survey, and cost-benefit analyses. This research will contribute to knowledge of the implications of health insurance coverage on ALL cancer care in young adults and inform policy-relevant solutions, including determining whether patients are bypassing an SCC for treatment at a more distant facility, calculating estimates of insurance acceptance and access challenges at ALL treating facilities and identifying the financial implications of shifting care to SCCs with demonstrated survival improvements for this population.

Project Term: June 1, 2023 - May 31, 2026

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

Project Term: June 1, 2023 - May 31, 2026

Although they represent a major therapeutic progress for blood cancers, CAR-T cells and other T-cell based therapies are subject to eventual development of resistance to many patients. Natural killer (NK) cell-based therapies are highly active against many types of blood cancer cells which are resistant to T cells, but in our CRISPR studies death receptor signaling defects emerge as a common downstream mechanism of resistance to both T- and NK-cell therapies. Building on extensive pharmacological and genomic screens, this project will specifically examine the role of SMAC mimetics and JAK/STAT inhibitors in enhancing the response of blood cancer cells (e.g., multiple myeloma, leukemias) to CAR-T or NK cell therapies. We will place emphasis of studies with patient-derived samples in vitro (Integrated Functional Immune Profiling Platform) and in vivo, including humanized bone marrow-like scaffolds, to provide a translationally-relevant simulation of the potential of these compounds to enhance the clinical activity of cell-based immunotherapies in blood cancers.

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

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.

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

In up to half of patients with hematologic malignancies undergoing allogeneic stem cell transplantation, the trajectory of a smooth recovery toward cure is disrupted by acute graft-versus-host disease (aGVHD). Inspired by the role of intestinal microbial communities in aGVHD pathogenesis, we recently completed the largest fecal microbiota transplantation (FMT) trial to date in transplant recipients. We established the safety of standardized third-party FMT and characterized FMT effects on the microbiota, leading to the proposed randomized, placebo-controlled phase 2 trial of FMT to prevent aGVHD.

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

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

Project Term: July 1, 2023 - August 31, 2026

Inhibition of a tumor-triggered immune exhaustion pathway, termed PD-1 blockade, enables immune effector cells to attack cancers. In classic Hodgkin Lymphoma (cHL), PD-1 blockade is now a standard treatment for relapsed disease and a component of experimental frontline therapy. We have identified a major population of monocyte/macrophages in patients with cHL that inhibit tumor cell killing and limit the efficacy of PD-1 blockade. Our goal is to fully characterize these tumor-specific monocytes/macrophages and target their immunosuppressive and tumorigenic program for therapeutic benefit in patients with cHL and other lymphoid malignancies.

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

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.

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