Having completed my fellowship in surgical oncology, I have embarked upon a career in academic surgery, combining a clinical surgical oncology practice with basic science research in tumor immunology. I am seeking a career transition award to develop a cancer research program investigating neoadjuvant immunotherapy as an adjunct to surgical resection. I initially became interested in the anti-tumor immunity generated by in situ tumor destruction when I investigated the use of cryosurgery in the treatment of breast cancer. During a two-year NIH T32 laboratory research fellowship in the Department of Immunology at Roswell Park Cancer Institute under the mentorship of Dr. Richard Bankert, D.V.M., Ph.D., I investigated methods by which to augment anti-tumor immunity through co-stimulatory molecules such as 4-1BB, CTLA-4 and CD40. I also studied the systemic immune response generated by the sustained release of cytokines in the tumor microenvironment, and the effect this had on recurrence and metastases. This approach was accomplished by encapsulating biologically active cytokines with biodegradable poly-lactic acid microspheres (PLAM) and injecting them directly into the tumor. Utilizing a novel murine surgical model I developed, I was able to show that injection of tumors with IL-12 loaded PLAM prior to surgical excision resulted in decreased local recurrence, distant metastases and improved survival. These results have been improved upon further by the use of combination cytokine therapy consisting of IL-12 and GM-CSF. The clinical utilization of this approach to neoadjuvant immunotherapy, if proved effective, is more feasible and potentially more cost-effective than other attempts to harness the power of the immune system to improve survival. I plan to expand upon this novel approach by establishing the efficacy of an in situ tumor vaccination strategy that utilizes combination cytokine-loaded biodegradable microspheres to generate a tumor specific immune response, and investigate the underlying immune mechanisms of tumor rejection involved to better translate this approach to the human system. I will pursue this area of investigation as a full-time faculty member, with full commitment from the Department of General Surgery and the Division of Surgical Oncology at the University of Michigan Medical Center.
