Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma

Abstract

SUMMARY Genetically modified T cells expressing chimeric antigen receptors (CARs) demonstrate robust responses against lineage restricted, non-essential targets in 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-specific expression. The majority of CAR targets have been normal self-antigens on dispensable hematopoietic tissues or overexpressed shared antigens. Here, we established that abnormal self-antigens can serve as targets for tumor rejection. We developed a CAR that recognized cancer-associated Tn glycoform of MUC1, a neoantigen expressed in a variety of cancers. Anti-Tn-MUC1 CAR T cells demonstrated target-specific cytotoxicity and successfully controlled tumor growth in xenograft models of T cell leukemia and pancreatic cancer. These findings demonstrate the therapeutic efficacy of CAR T cells directed against Tn-MUC1 and present aberrantly glycosylated antigens as a novel class of targets for tumor therapy with engineered T cells.

Chimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy

“…Therefore, tumor-specific CAR targets need to be selected. Posey et al reported a CAR that targets an abnormal glycoform of MUC1, Tn-MUC1, which is specifically expressed by multiple types of tumors but not on the cellular surface of normal human tissues [74] . Thus, this approach allowed the selection of aberrantly glycosylated antigens and constitutes a safer alternative to tumor-associated antigens for CAR-based therapy.…”

Immunotherapy: Pancreatic Cancer and Extrahepatic Biliary Tract Cancer

“…Targeting against the tumor antigen mesothelin [51, 52], carcinoembryonic antigen [53], prostate stem cell antigen [54, 55], HER2 neu, CD24 [56], CD133 and mucin-1 (MUC-1) [57] has shown activity in preclinical tumor models. Currently, multiple clinical phase I and II trials using CAR T-cell therapy targeting prostate stem cell antigen (e.g.…”

The Flipside of the Power of Engineered T Cells: Observed and Potential Toxicities of Genetically Modified T Cells as Therapy

“…Although most CAR targets have been limited to natural cell-surface antigens in the form of proteins, it is possible to target post-translational modifications of proteins 26,27 and glycosphingolipids with CARs. 28 T cells can also be genetically modified with natural or engineered T cell receptors (TCRs), which recognize peptides presented in the context of major histocompatibility complex (MHC).…”