Effect of modulation of the hostile tumor microenvironment through adoptive transfer of IL-12 expressing MUC-16 targeted T cells on ovarian tumors in vivo.

Abstract

2586 Background: T cells may be genetically modified to recognize tumor associated antigens (TAAs) through the introduction of genes encoding artificial T cell receptors termed chimeric antigen receptors (CARs). MUC16 (CA125) is an antigen over-expressed on ovarian carcinomas and a serum marker for the diagnosis of ovarian cancer. We have previously demonstrated enhanced antitumor efficacy of CAR+ T cells further modified to secrete IL-12. We therefore tested whether MUC-16 targeted T cells further modified to express IL-12 would exhibit an enhanced antitumor efficacy in a syngeneic immunocompetent tumor model of ovarian cancer. Methods: We have constructed SFG retroviral vectors encoding the second (4H11m28mz) generation CARs as well as IL-12 modified CAR (4H11m28mz/mIL12) targeted to the retained extra-cellular domain of MUC16, termed MUC-CD. We demonstrated an antitumor efficacy of these T cells in a syngeneic tumor model using the C57BL6 (B6) mice intraperitoneally (i.p.) injected with ID8(MUC-CD) tumor cells. Results: In our studies treatment of mice bearing established ID8(MUC-CD) ovarian tumor with MUC-CD specific T cells expressing IL-12 gene, in contrast to T cells targeted to MUC-CD alone, fully eradicate highly advanced intraperitoneal ovarian tumors. Significantly, we found that mice treated with 4H11m28mz/mIL12 T cells had increased number of modified T cells in the peritoneum at day 4 and 7 with increased recruitment of endogenous T cells to the site of the tumor when compared to controls and mice treated with 4H11m28mz T cells. The observed antitumor effect did not required prior lymphodepletion and was well tolerated in treated mice. Conclusions: CAR modified T cells targeted to the MUC-16 antigen efficiently eradicate orthotopic ovarian cancer in syngeneic immunocompetent mice with markedly enhanced antitumor efficacy seen in those mice treated with CAR+ T cells further modified to secrete IL-12. These data support future clinical trials utilizing adoptive T cell therapy in patients with relapsed ovarian cancer.