Posey, AD, Schwab, RD, Boesteanu, AC, Steentoft, C, Mandel, U, Engels, Boris, Stone, JD, Madsen, TD, Schreiber, K, Haines, KM, Cogdill, AP, Chen, TJ, Song, D, Scholler, J, Young, R, Keith, B, Schreiber, H, Clausen, H, Johnson, LA and June, CH (2016) Validation of Abnormal Self-Antigens as Targets for Tumor Rejection by CAR T Cells. Science Translational Medicine, 44 (6). pp. 1444-1454. ISSN 1097-4180

Abstract

Aberrant posttranslational modifications of cellular proteins represent a broad repertoire of putative tumor-specific targets. In general, vaccines targeting these aberrant self-antigens have only generated modest immune responses. In contrast, genetically modified T cells that express chimeric antigen receptors (CARs) demonstrate robust responses against associated targets, and have been clinically effective in treating hematologic cancers. However, in solid tumors the full potential of CAR T cell therapy is limited by the availability of cell surface antigens with sufficient cancer-associated expression to which single-chain variable fragments (scFvs) can be designed. Thus, the majority of CAR targets to date have been normal self-antigens on dispensable hematopoietic tissues or overexpressed shared antigens. Here, we validate abnormal self-antigens as targets for tumor rejection through the use of a novel CAR. We targeted the cancer-associated Tn glycoform of MUC1 in a variety of cancers. The anti-Tn-MUC1 CAR demonstrated target-specific cytotoxicity and successfully controlled tumor growth in xenograft models of T cell leukemia and pancreatic cancer. These finding demonstrate the therapeutic efficacy of CAR T cells directed against abnormal self-antigens and the potential for targeting tumor-specific glycoproteins in future cancer immunotherapies.

Item Type:	Article
Date Deposited:	17 Aug 2016 00:45
Last Modified:	17 Aug 2016 00:45
URI:	https://oak.novartis.com/id/eprint/26527