Abstract IA09: Reprogramming T cells for adoptive immunotherapy of ovarian cancer.
Authors: Odunsi Kunle 
Published: May 2016

The goal of our studies is to generate robust and long-lasting tumor-specific T cell responses for durable tumor regression in patients with epithelial ovarian cancer (EOC). While the majority of women with advanced stage EOC initially respond to surgery and first-line chemotherapy, more than 70% of patients eventually die of recurrent disease within 5 years of diagnosis. In an effort to generate tumor-associated antigen (TAA) specific T cells for the treatment of EOC patients, our team has identified NY-ESO-1 as the prototypic TAA for immunotherapy in ovarian cancer. In clinical trials of cancer vaccines conducted by our group, although active immunization targeting NY-ESO-1 can generate TAA specific effector T cells, the long term control of ovarian cancer is infrequent. This is primarily because of the relatively low magnitude and short in vivo lifespan of the vaccine-elicited T cells limited long-term tumor control in the patients. Consequently, we have focused on genetically re-engineering T cells to express a NY-ESO-1 specific CD8+ T cell receptor (CD8TCR), followed by adoptive transfer of these cells into EOC patients. Although this approach led to large numbers of circulating tumor antigen specific T cells and tumor regression, the strategy is hampered by the relatively short lifespan of the effector CD8+ T cells. These results indicate that lack of sustained expansion of long lasting, durable tumor specific T cells is a major obstacle for successful adoptive T cell therapy.

In preliminary studies, we have focused on CD4+ T cells as the major driver of anti-tumor immunity. In order to augment the in vivo persistence of the engineered CD8TCR cells, we have cloned a distinct subset of human CD4+ Th1 cells that directly recognize NY-ESO-1 naturally presented by MHC class II on cancer cells. In addition, these tumor-recognizing CD4+ T cells (TR-CD4TCR) potently provide help to CD8TCR cells in an antigen-presenting cell (APC) independent fashion and amplify the anti-tumor effects of CD8+ T cells. In contrast, their conventional TAA-specific CD4+Th1 counterparts (non-tumor recognizing, NTR-CD4), require APCs for their activation. Direct cognate interaction between TR-CD4 and cancer cells triggers the release of an array of effector molecules which inhibit tumor growth and amplify the anti-tumor effects of CD8+ T cells. We have also demonstrated that human hematopoietic stem/progenitor cells (hHSC) can be genetically re-programmed for continuous generation of long lived tumor-specific T cells in an NSG mouse model. We propose a novel clinical application of hHSCs for the continuous (possibly lifelong) source of anti-cancer immune cells that will provide sustained attack against cancer cells.

Citation Format: Kunle Odunsi. Reprogramming T cells for adoptive immunotherapy of ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA09.