Grant number: RGS-12-075-01-LIB

Principal Investigator: SangKon Oh, PhD

Funding Organization: American Cancer Society

Project Start: January 1, 2012

Project End: December 31, 2015

Abstract:

Dendritic cells (DCs) are the major immune inducers/regulators. Clinical trials testing first-generation DC vaccines have shown certain levels of tumor regressions in a fraction of patients. However, clinical efficacy of current vaccine approaches is limited, mainly due to:

• Tumors invade the immune system by means of regulatory T cells (Tregs).

• The potency of therapeutic immunity elicited by current vaccine models may not be sufficient enough to eradicate tumors.

To improve clinical efficacy, we need to design novel strategies that can efficiently boost host immunity to cancer, help overcome Tregs and allow the breakdown of the immunosuppressive tumor microenvironment. This can be achieved by developing combination therapies targeting those two major components. DC-targeting vaccine models were pioneered by M. Nussenzweig’s and R. Steinman’s groups at Rockefeller University. In animal models, targeting a minute amount of antigens to in vivo DCs resulted in dramatic improvement of antigen-specific T cell immunity. At BIIR, we have developed a platform technology for targeting antigens directly to human DCs. Human in vitro and non-human primate in vivo studies show that vaccines based on DC-targeting elicit potent and broad CD4⁺ and CD8⁺ T cell responses at low antigen doses. In collaboration with Dr. Liu (MD Anderson Cancer Center), we have recently found that an agonistic anti-human OX40 mAb significantly inhibited antigen-specific Treg responses in vitro.

OBJECTIVES/HYPOTHESIS: Herein, we propose to test the immune and clinical (in animal models) efficacy of an antibody-based combination immunotherapy. 1) A novel DC vaccine based on in vivo targeting antigens directly to human DCs. We propose to target CD40 to exploit both the antigen delivery component and the strong DC activation signal. Anti-CD40 mAb is currently being humanized for our future clinical trials. 2) Anti-OX40 mAb targeting immunoregulatory molecules on T cells. This antibody targets Tregs. We hypothesize that the immune and clinical efficacy of recombinant vaccines composed of anti-CD40 mAb and prostate specific antigen (PSA) will be improved when combined with antibodies targeting Tregs.