UG3CA290241

CD28-KITV CAR T cells with PD-1 dominant negative receptor - project abstract

The success of chimeric antigen receptor (CAR) T-cell therapy in solid tumors requires antigen targets with no on-target, off-tumor toxicity, effective tumor infiltration, cytotoxicity and proliferation in an immunosuppressive environment, and revival of antigen stress-induced exhausted CAR T cells.

We translated CD28-costimulated CARs (M28Z) that target mesothelin (MSLN), a cancer-associated antigen that we have documented expression in majority of solid tumors; 64 patients have been treated to date, with no on-target, off-tumor toxicity.

Having demonstrated that regionally administered CAR T cells avoid pulmonary sequestration and benefit from early antigen-activated CD4 helper CAR T-cell function, we delivered CAR T cells intrapleurally in patients with malignant pleural mesothelioma (MPM), promoting tumor infiltration.

To address T-cell exhaustion, we either treated patients with anti-PD1 agent after CAR T cells or employed tumor-specific checkpoint blockade by CAR T-cell intrinsic PD1 dominant negative receptor (PD1DNR); 34 patients have been treated to date, with no CAR- or PD1DNR-related toxicities and with responses by imaging, and increased survival.

To promote IFN-mediated cytotoxicity shown to be essential for solid tumor killing, we exploited a c-KIT mutation, D816V (KITV), as a costimulatory domain. KITV CAR T cells show antigen-activation induced IFN signaling, enhanced cytotoxicity, and when added as signal 3 to CD28 (signal 2), provide a synergistic function, resist TGFSS-mediated suppression, and prolong functional persistence.

Clinically available kinase inhibitors provide an on/off, tunable safety switch for KITV CAR T cells. To effectively deliver these next-generation CAR T cells to solid tumors, we developed a translational strategy of non-ablative, tumor-targeted radiation therapy (RT) to generate a chemokine gradient that facilitates systemically administered CAR T-cell chemotaxis, tumor infiltration, proliferation, and persistence.

Herein, we seek to translate the M28ZKITV-PD1DNR CAR T cells to address key limitations in solid tumor cell therapy. In UG3 phase, we will explore the hypothesis that PD1DNR checkpoint blockade extends beyond tumor cells and counteracts PDL1-expressing M2 macrophages with immune suppressor function (Aim 1).

We will define optimal regimen of non-ablative, tumor-targeted RT to promote tumor infiltration of systemically administered CAR T cells, achieving efficacy similar to that with regional delivery. In Aim 3, we will submit an IND application, a process with which we are familiar and have track record of success.

In UH3 phase, we will conduct a phase I study to investigate the safety, functional activity and efficacy, and markers of response in patients with MPM. The significance of our approach lies in its effective combination of solid tumor-specific– SCFV that is on-target and safe (MSLN), costimulatory domains (CD28, KITV), checkpoint blockade (PD1DNR), and a strategy of promoting solid tumor-infiltration (RT) of CAR T cells.

The impact of our proposal extends beyond MPM (>150,000/year pleural cancers in the U.S.); majority of aggressive solid tumors express MSLN.

Sloan-Kettering Institute For Cancer Research

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]

New York, New York 100656007 United States

Single Zip Code

Cancer Adoptive Cellular Therapy Network (Can-ACT) for Adult Cancers (UG3/UH3 Clinical Trial Required) (RFA-CA-22-028)

Amendment Since initial award the total obligations have increased 105% from $1,491,519 to $3,061,861.