R37CA266344

Towards Safer and More Effective CAR-T Cell Therapy through the Modulation of Myeloid Cytokines - Project Summary

Despite the impressive activity of Chimeric Antigen Receptor (CAR-T) cell therapy in the treatment of B-cell malignancies, the therapy is limited by the development of Cytokine Release Syndrome (CRS) and neurotoxicity, as well as lower rates of durable responses.

While CRS is related to extreme elevation of cytokines associated with T cell expansion, the exact etiology of neurotoxicity is unknown, and no options for treatment of neurotoxicity are available. It has, however, become apparent that inhibitory myeloid cells and cytokines contribute to both CAR-T cell toxicities and resistance.

We have identified Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) as a dominant driver for CAR-T cell toxicity and inhibition of their functions. Our robust preclinical data indicate that GM-CSF inhibition reduces monocyte activation, enhances CAR-T cell functions, and prevents the development of both CRS and neurotoxicity in a novel xenograft model for CAR-T cell-associated toxicities.

Our additional studies suggest that GM-CSF disruption in CAR-T cells ameliorates their apoptosis, independent of its effect on myeloid cells. These findings were corroborated when we utilized GM-CSF depletion as a therapeutic strategy in patients with cytokine storm and severe Coronavirus Disease 2019 (COVID-19). Based on this work, a Phase 1/2 multi-center study of GM-CSF neutralization after CAR19 cell therapy was launched.

Our central hypothesis is that depletion of GM-CSF results in modulation of myeloid cell behavior, amelioration of CAR-T cell activation, reduction of CAR-T cell-associated toxicities, and enhancement of their efficacy. We will leverage our laboratory tools, novel preclinical models, and samples from this clinical trial to test our hypothesis.

In Aim 1 of this project, we will examine the interactions between GM-CSF and monocytes after CAR-T cell therapy. In Aim 2 of this project, we will study the effect of GM-CSF directly on CAR-T cells, and Aim 3 will test how these changes affect toxicity and efficacy of CAR19 cell therapy in the novel Phase 1/2 clinical trial.

Completion of these aims will identify novel insights into the toxicity and activity of CAR-T cells and will develop a new strategy to prevent CAR-T cell-associated neurotoxicity and CRS, potentially enabling the outpatient administration of CAR-T cell therapy.

Mayo Clinic

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

Rochester, Minnesota 559050001 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 473% from $606,332 to $3,471,859.