Personalized T cell therapy for metastatic colon cancer.

Abstract

e15183 Background: Current immunotherapies fail to benefit patients with colon cancer, largely due to high molecular heterogeneity and low frequencies of tumor infiltrating lymphocytes. In this study, we are addressing this limitation via a novel technology to expand patient tumor specific T cells ex-vivo, using patient’s matched tumor and peripheral blood mononuclear cells (PBMCs). This technology utilizes tumor membrane vesicles (TMVs) made from excised tumor tissue, as a source of tumor associated antigens, and further modified to express IL-12 and B7-1 for ex-vivo expansion of tumor specific T cells. Additionally, the T cells are cultured with PI3K delta inhibitor (idelalisib) and vasoactive intestinal peptide antagonist (VIPhyb) to increase yield, polyfunctionality and in-vivo persistence. Methods: Matched tumor and blood were collected from consented colon cancer patients. TMVs were prepared from excised tumors by homogenizing and centrifuging the tumor over a sucrose gradient. TMVs were then made to express glycosyl phosphatidylinositol (GPI) linked IL-12 and B7-1 (decorated TMV) via a proprietary protein transfer technology. PBMCs isolated from matched blood were cultured in media with 10ug/ml decorated TMV with/without VIPhyb(3uM) and idelalisib (100nM) for 14 days. T cells were then phenotyped for percentage of IFN gamma secreting CD4+ and CD8+ T cells and injected into PDX mice bearing matched tumors (2 doses of 1 million and 4 million cells, 20 days apart). Results: 14 days after expansion, T cells expanded with decorated TMVs+VIPhyb+idelalisib (TMVs+drugs) resulted in significantly increased number of IFN gamma secreting CD8+ T cells (25% of T cells), when compared to T cells treated with decorated TMVs without VIPhyb and idelalisib (13% of T cells). Further, when injected to PDX mice bearing matched tumors, and followed for differences in tumor growth, we observed that on day 30 after T cell injection, while the tumor volumes increased 4.5-fold in the untreated group, the tumors in the TMVs+drugs group only increased 2.8-fold. Conclusions: In this study, we have thus developed a novel technology to expand patient tumor specific T cells ex-vivo, for adoptive T cell therapy against metastatic colon cancer.