R01CA303538

NATURAL KILLER CELLS SUBVERT IMMUNE CHECKPOINT THERAPY OF TUMORS - ABSTRACT SINCE NATURAL KILLER (NK) CELLS CAN KILL TUMOR CELLS THAT ALSO STIMULATE NK CELL PRODUCTION OF CYTOKINES, THERE IS INTENSE CURRENT INTEREST ON HOW TO HARNESS NK CELLS TO ADVANCE IMMUNOTHERAPY OF CANCER. MOST STRATEGIES GUIDING SUCH WORK FOCUS ON MARKEDLY ENHANCING NK CELL RESPONSES TO TUMORS. HOWEVER, OUR UNDERSTANDING OF NK CELL BIOLOGY IN THE CONTEXT OF IMMUNE CHECKPOINT THERAPY (ICT) OF CANCER IS POORLY UNDERSTOOD. CONTRARY TO EXPECTATIONS, HERE THE APPLICANT’S LABORATORY PRESENTS PRELIMINARY DATA INDICATING THAT ANTIBODY-MEDIATED NK CELL DEPLETION OR GENETIC ABSENCE OF NK CELLS ENHANCED ICT IN MICE, SUGGESTING NK CELLS SUBVERT ICT. MOREOVER, TRANSFER OF NK CELLS INTO THE TUMOR ITSELF IN MICE GENETICALLY LACKING NK CELLS RESTORED SUBVERSION OF ICT. FURTHERMORE, ANTI-NKG2D ALSO ENHANCED ICT. FINALLY, THE APPLICANT PROVIDES EVIDENCE FROM HUMAN TUMOR DATABASES THAT A SIMILAR PROCESS MAY BE OCCURRING IN PATIENTS. THUS, NK CELLS SUBVERT ICT AND NKG2D APPEARS TO BE INVOLVED IN THIS PROCESS. THEREFORE, THE SPECIFIC AIMS OF THIS PROPOSAL ARE TO: 1) ELUCIDATE EFFECTOR MECHANISM(S) BY WHICH NK CELLS CONSTRAIN ICT; 2) EVALUATE CONTRIBUTION OF NKG2D; AND 3) TRANSLATE MOUSE FINDINGS TO HUMAN TUMORS. TAKEN TOGETHER, THIS PROPOSAL WILL LEAD TO INCREASED INSIGHT ON THE ROLE OF NK CELLS IN ICT AND WILL HELP GUIDE NEW STRATEGIES TO MODULATE NK CELLS FOR IMPROVED CANCER IMMUNOTHERAPY.

Washington University

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]

Missouri United States

State-Wide

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