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

TY - JOUR

T1 - Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma

AU - Posey, Avery D

AU - Schwab, Robert D

AU - Boesteanu, Alina C

AU - Steentoft, Catharina

AU - Mandel, Ulla

AU - Engels, Boris

AU - Stone, Jennifer D

AU - Madsen, Thomas D

AU - Schreiber, Karin

AU - Haines, Kathleen M

AU - Cogdill, Alexandria P

AU - Chen, Taylor J

AU - Song, Decheng

AU - Scholler, John

AU - Kranz, David M

AU - Feldman, Michael D

AU - Young, Regina

AU - Keith, Brian

AU - Schreiber, Hans

AU - Clausen, Henrik

AU - Johnson, Laura A

AU - June, Carl H

N1 - Copyright © 2016 Elsevier Inc. All rights reserved.

PY - 2016/6/21

Y1 - 2016/6/21

N2 - 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. Posey and colleagues developed a CAR T cell therapy to break immune tolerance to solid tumors by targeting an aberrantly glycosylated, cancer-specific glycoprotein in multiple cancer histotypes and demonstrated efficacy and safety in tumors as diverse as leukemia and pancreatic cancer.

AB - 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. Posey and colleagues developed a CAR T cell therapy to break immune tolerance to solid tumors by targeting an aberrantly glycosylated, cancer-specific glycoprotein in multiple cancer histotypes and demonstrated efficacy and safety in tumors as diverse as leukemia and pancreatic cancer.

U2 - 10.1016/j.immuni.2016.05.014

DO - 10.1016/j.immuni.2016.05.014

M3 - Journal article

C2 - 27332733

SN - 1074-7613

VL - 44

SP - 1444

EP - 1454

JO - Immunity

JF - Immunity

IS - 6

ER -