R01CA267694

Mechanistic Factors Limiting Utility of Adenovirus Vectors for Treatment of Neoplas

Abstract

Adenovirus-based vectors are a very attractive platform for the development of novel drug candidates for the treatment of numerous genetic diseases and cancer. Currently, the prevailing view of requisites for effective virus-based cancer therapeutics includes:

I) A potent cytotoxic capacity to trigger virus-mediated killing of as many tumor cells as possible in the shortest period of time, and
II) The capacity for stimulating adaptive anti-tumor immune response.

While early efforts to develop potent oncolytic therapeutics were primarily focused on harnessing or even increasing virus-mediated tumor cell cytotoxicity, new data suggest that in vivo, the therapeutic efficacy of viruses with low cytotoxic capacity is comparable or even better than that of viruses which are highly effective at killing cancer cells in vitro. The mechanistic factors underlying this mismatch between efficacy and potency in vivo remain poorly understood.

While evaluating the therapeutic efficacy of systemically administered adenovirus-based vectors in a mouse model of disseminated lung cancer, we found that virus dose escalation leads to a reduction in median survival of tumor-bearing mice. In mice that developed a 'non-responder' phenotype, myeloid cells become highly activated in response to adenovirus administration. Based on these findings, we propose the novel concept of a "reparative call", whereby efficient tumor cell killing by the virus triggers activation of tumor-associated myeloid cells, which in turn secrete pro-tumorigenic growth factors, triggering accelerated tumor growth.

This project is designed to comprehensively address mechanistic aspects of this concept by analyzing how cytotoxic potency may affect the efficacy of systemic virotherapy with adenovirus-based vectors. We will determine the mechanistic role of tumor-derived IL-33 in driving myeloid cell activation and will develop novel adenovirus vectors expressing soluble IL-33R to block IL-33-dependent tumor cell activation. We will further analyze the therapeutic efficacy of soluble IL-33R-expressing adenovirus vectors in combination with clinically relevant drugs that target myeloid cells and the PD-1 pathway.

The successful completion of this project will significantly advance our understanding of fundamental factors that are critical for the effective clinical translation of adenovirus-based vector systems for the therapy of neoplastic disease.

Emory 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]

Atlanta, Georgia 303221119 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 386% from $632,232 to $3,070,508.