Fc-enhanced CD40 agonist antibodies for immune modulation of the tumor microenvironment

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Project Summary/Abstract Candidate: The PI, an Instructor in Clinical Investigation at the Rockefeller University, has developed a 5-year career development plan building upon his scientific background in immunology and clinical training in medical oncology. His mentor, Dr. Jeffrey Ravetch, is an internationally recognized expert in Fc receptors. The PI has strategically planned to address the necessary training and mentoring required for his successful career transition to independence through select coursework and a robust mentoring plan. An advisory committee composed of leaders in the field will not only ensure that the PI’s research project progresses as planned, but also is recognized by promotion and leads to independent research funding. This exciting research project is also sufficiently different from that of his mentor’s in order to avoid competition or overlap. Research plan: The recent success of immunotherapy has re-invigorated an interest in harnessing a patient’s own immune system against cancer. While therapies blocking PD-1 have improved the overall survival of patients with bladder cancer, a number of patients don’t derive clinical benefit. My studies have focused on optimizing immune stimulating agents targeting CD40. CD40 plays a key role in the activation of antigen presenting cells (APCs) and the generation of tumor specific T cells. Agonistic anti-CD40 antibodies have been proposed as an efficient approach to promote the maturation of APCs in patients; however, they were toxic with little activity. A likely explanation for this limited activity was provided by our prior studies demonstrating an absolute requirement for the antibody Fc to bind to the inhibitory Fc receptor, FcRIIB. Using this knowledge, we Fc-engineered lead clinical candidate, 2141-V11, which had superior anti-tumor efficacy. Additionally, using an in situ vaccination approach we demonstrated potent anti-tumor activity without evidence of toxicity. We are now investigating the role CD40 in the tumor microenvironment (TME) and how it can be targeted for the treatment of bladder cancer. This is because current immunotherapy in the form of intravesical Bacillus Calmette-Guerin (BCG) is not effective for a large proportion of patients affected by this disease. Our preliminary data support a role for CD40 in bladder tumors and reversal of T cell phenotypes thought to be targeted by anti-PD-1 therapies. Thus, CD40 antibodies, alone or in combination with “checkpoint blockade”, could help improve outcomes in patients not responding to intravesical BCG therapy. Building on our groups extensive experience in studying antibody therapies and access to unique tissue specimens, we now aim to test the hypothesis that 2141-V11 will target dendritic cells in the TME to promote successful anti-tumor immunity.