Abstract 5338: Metastatic colorectal cancer cells from patients previously treated with chemotherapy are sensitive to T cell killing mediated by CEA/CD3-bispecific T cell-engaging BiTE antibody

Abstract

Abstract Carcinoembryonic antigen (CEA; CD66e, CEACAM5) is a well-characterized tumor-associated antigen that is frequently and uniformly over-expressed in human carcinomas. A novel bispecific single-chain antibody of the bispecific T cell engager (BiTE) class named MEDI-565 (also known as MT111) was generated by genetic engineering. MEDI-565 binds CEA on cancer cells and CD3 present on T cells; such binding mediates T cell killing of cancer cells expressing CEA. However, MEDI-565 effectively mediates the killing of cancer cells only if it binds concurrently to CEA on a cancer cell and to CD3 on a T cell. We hypothesized that metastatic human colorectal cancer (CRC) previously treated with conventional chemotherapy would be sensitive to T cell-mediated killing if T cells of a sufficient magnitude could be activated against the tumor. To test this hypothesis, we selected MEDI-565 to redirect a large number of polyclonal T cells against tumors expressing CEA instead of using a cancer vaccine approach that, in general, is anticipated to elicit few antigen-specific T cells in humans. We analyzed proliferation and lysis of CEA-positive CRC specimens that had survived prior systemic chemotherapy and biologic therapy to determine if they could be killed by patient T cells engaged by MEDI-565 in vitro. The mechanism of redirected T cell killing was also investigated. At low concentrations (0.1 to 1 ng/mL), MEDI-565 plus T cells caused reduced proliferation and enhanced apoptosis of CEA-positive human CRC specimens. High levels of soluble CEA (≤ 1,000 ng/mL) did not affect MEDI-565-induced T cell killing of cells expressing CEA, suggesting that endogenous circulating CEA may not impair the clinical activity of MEDI-565 in patients. Cancer cell lines expressing CEA remained sensitive to T cell mediated killing despite repeated exposure to T cells and MEDI-565. These results suggest that MEDI-565/T-cell treatment may not induce escape mechanisms in cancer cells, and, thus, might be suitable for long-term and repeated treatment. Granzyme B and perforin were implicated as potential mediators of MEDI-565-induced T cell killing. Furthermore, MEDI-565 activated T cells to secrete both Tc1 (Th1) and Tc2 (Th2) type cytokines. This study demonstrates for the first time that metastatic CRC specimens derived from patients previously treated with conventional chemotherapy can be lysed by patient T cells. Clinical testing of cancer immunotherapies such as MEDI-565 that result in exposure of tumors to large numbers of T cells is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5338.