R01CA256898

Targeting B7-H3 in Ovarian Cancer - Abstract

Remarkable clinical responses have been reported in B-cell malignancies by adoptive transfer of T cells redirected with a chimeric antigen receptor (CAR) specific for the CD19 antigen. However, developing CAR-Ts for the treatment of solid tumors, including ovarian cancer (OC), is challenging because:

(1) OC-associated antigens that are targetable by CAR-Ts are limited, generally not exclusively expressed by OC, and act as passengers, not as drivers of tumorigenesis, allowing for antigenic drift;

(2) OC tumor microenvironment (TME) is highly immunosuppressive.

In this proposal, we aim at solving these critical issues. We have identified B7-H3 (CD276) as a suitable target for chimeric antigen receptor (CAR) T cells in OC. B7-H3 is a tumor-promoting transmembrane protein aberrantly expressed in 60% to 93% of pancreatic cancer, melanoma, leukemia, breast, prostate, and OC, while limited expression is seen on normal healthy tissues.

We have developed and tested B7-H3.CAR-Ts in xenogeneic and immunocompetent tumor models, showing antitumor activity in several tumor models, including OC, and safety. Thus, in Aim 1, we propose to conduct a Phase I clinical study in patients with OC to assess safety and antitumor activity of autologous B7-H3.CAR-Ts inoculated intraperitoneally. An IND (IND19641) for this study has been obtained at the University of North Carolina, and clinical-grade reagents to manufacture B7-H3.CAR-Ts are in hands.

In Aim 2, we propose to conduct a comprehensive immunologic analysis of tumor biopsies and ascites collected from patients enrolled in the study before and after treatment to assess antigen loss and immunologic perturbation of the TME in OC.

In Aim 3, we propose to reprogram tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSC) of the OC TME to a non-immunosuppressive state by using potent and orally bioavailable TAM RTK small molecule inhibitors developed at the University of North Carolina (IND128236). We will thus perform preclinical studies to evaluate whether TAM RTK signaling inhibition in macrophages and MDSC would favor the antitumor activity of B7-H3.CAR-Ts in a syngeneic model of OC. If successful, this strategy will be included in a second phase of the proposed Phase I clinical study with B7-H3.CAR-Ts.

University Of North Carolina At Chapel Hill

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]

Chapel Hill, North Carolina 275996136 United States

Single Zip Code

National Cancer Institute's Investigator-Initiated Early Phase Clinical Trials for Cancer Treatment and Diagnosis (R01 Clinical Trials Required) (PAR-18-560)

Amendment Since initial award the End Date has been extended from 01/31/26 to 01/31/27 and the total obligations have increased 382% from $632,310 to $3,045,536.