Abstract PO083: Treatment of CEA-positive solid tumors with anti-CEA chimeric antigen receptor T-cells in CEA transgenic mice

Abstract

Chimeric antigen receptors (CARs) combine specificity of antibody to target antigen on cancer cells with the potent cytotoxic activity of T-cells without the need for MHC recognition. Chimeric antigen receptor (CAR) T-cells that were designed to express the single chain variable fragment binding domain of human anti-CEA antibody BW431/26 on mouse splenocytes were able to reduce CEA-expressing pancreatic adenocarcinoma tumor in CEA-transgenic (CEAtg) mice without significant off-target effects (Chmielewski et al., 2012). In this study, an anti-CEA CAR construct derived from murine anti-CEA antibody (T84.66) expressed on human T-cells targeted CEA+ colon carcinoma cells (LS174T/CEA and MC38CEA) with high specificity in vitro. When co-incubated with CEA-positive or CEA-negative mouse cancer cells, anti-CEA CAR expressed on mouse T-cells also specifically targeted CEA-positive cancer cells in vitro. Compared to mock T-cells control, anti-CEA CAR T-cells injected intravenously delayed subcutaneous MC38CEA tumor growth in CEA-transgenic mice (CEAtg). Lymphodepletion via cyclophosphamide injected before anti-CEA T-cells injection further delayed subcutaneous MC38CEA tumor growth and delayed orthotopic CEA+ breast carcinoma (E0771CEA) tumor growth in CEAtg mice. To improve the therapeutic potential of anti-CEA CAR T-cells, IL2 conjugated to humanized anti-CEA antibody (M5A-IL2, ICK) was interperitoneally injected after anti-CEA CAR T-cells into lymphodepleted CEAtg mice. A single injection of ICK after anti-CEA CAR T-cells delayed subcutaneous MC38CEA tumor growth even further. Two injections of ICK after anti-CEA T-cells delayed orthotopic E0771CEA tumor growth. Four injections of ICK after anti-CEA CAR T-cells eradicated subcutaneous MC38CEA tumors. These data show the therapeutic potential of anti-CEA CAR T-cells to target CEA-positive tumors. Citation Format: Seung Cha, Paul Yazaki, Christine Brown, John Shively. Treatment of CEA-positive solid tumors with anti-CEA chimeric antigen receptor T-cells in CEA transgenic mice [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO083.

Tumor-associated antigen targets for novel immune-based strategies in prostate cancer

“…Recent studies have identified cell adhesion molecule 5, CEA (CEACAM5), as another highly expressed antigen specific to NEPC, and CEACAM5 may serve as a target TAA for future drug development. In vitro studies have demonstrated the successful creation of anti-CEA CAR-T cells with tumor growth delay and eradication [74,121,122] . While immunotherapy targeting the treatment of NEPC is in its early stages, there is an urgent and unmet need for novel therapies in this histology and future immunotherapy studies are likely to be forthcoming.…”

Novel Redirected T–Cell Immunotherapies for Advanced Prostate Cancer

“…Lee et al recently demonstrated in vitro support for the rational targeting of NEPC with CAR T cells. In addition, there have been recent promising in vitro studies showing successful application of anti-CEA CAR T cells in CEA-positive solid tumors further supporting CEA as a potential target for NEPC(67).…”