Targeted delivery of a VEGF‐blocking scFv by CD70 CAR‐T cells to enhance anti‐tumor activity in renal cell carcinoma

PROJECT SUMMARY Although chimeric antigen receptor (CAR)-T cells drive dramatic and durable remissions in patients with B-cell malignancies, responses in solid tumors have been more challenging. There is a dearth of highly effective “armoring” strategies for CAR-T cells to generate additional proteins that augment CAR-T cell function and

modulate the tumor microenvironment (TME). Our long-term goal is to develop safe and effective CAR-T cell therapies for solid tumors. The overall objective is to determine the effect of locally secreted VEGF blockade on CD70 CAR-T cell function, safety, and anti-tumor efficacy in renal cell carcinoma (RCC). Our central

hypothesis is that locally secreted VEGF blockade will prevent CAR-T cell exhaustion while blocking angiogenesis/tumor growth, and pathologic endothelial activation. The underlying rationale is that determination of the preclinical therapeutic efficacy and associated mechanisms of locally secreted VEGF-

blockade will offer a strong scientific framework for new strategies to cancer therapy. To attain the overall objective, we will pursue two specific aims: (1) Determine the effect of secreted VEGF blockade on CD70- CAR-T cell biology ; and (2) Define the capacity for CD70-CAR-T cells with secreted VEGF blockade to

modulate RCC tumor proliferation, angiogenesis, and endothelial activation in vivo. Approaching the project, the candidate will examine each side of the immune synapse, in turn, by (1) defining the effects of anti-VEGF single chain variable fragment (scFv) secretion on CAR-T cells through the underlying CD70 CAR-T biology

and honing in on the site of actions of the VEGF-scFv (paracrine, autocrine, or intracrine) (Aim 1), and (2) determining the effects of anti-VEGF scFv secretion on RCC tumor cells, angiogenesis, and endothelial activation via in vivo orthotopic RCC tumor models, cytokine release syndrome models, and VEGF-blockade

cardiovascular toxicity models (Aim 2) The applicant, Dr. Mark Leick, an oncologist at the Massachusetts General Hospital (MGH) spends 80% of his time in translational research and 20% in clinical practice caring for patients with cancer. He has outlined a five-year career development plan consisting of coursework,

conferences, seminars, and structured mentoring in experimental design, mouse modeling, angiogenesis and VEGF signaling pathways, CAR-T signaling, and renal cell carcinoma to acquire the necessary skills required to perform his research and to reach his goal of becoming an independent investigator in translational

research. His research is directly relevant to the mission of the NCI to conduct cancer research to advance scientific knowledge and help all people live longer healthier lives using immune cell therapies. Supervising Dr. Leick’s mentorship and training is Dr. Marcela Maus, a worldwide leader in cellular immunotherapy. Dr. Leick

will conduct this research at MGH and leverage the exceptional research and teaching environments of his scientific advisory committee (MGH, Dana Farber Cancer Institute, Beth Israel Deaconess Medical Center, and Boston Children’s Hospital).