To overcome on-target, off-tumor toxicity caused by CAR T cell therapy targeting carcinoembryonic antigen (CEA) in colon cancer, Sandberg and Wang et al. developed a modular dual-signal system (Tmod) consisting of a third-generation CEA CAR construct combined with an A*02-specific scFv blocker module, providing an OFF-switch for HLA-A*02-expressing cells. A*02 expression on Tmod was reduced using shRNA to prevent cis inhibition. In vitro experiments showed that Tmod were tumor-specific, had low off-tumor activity, and could sequentially switch between ON and OFF states. The tumor-specific activity was confirmed in mouse xenograft models.
Contributed by Maartje Wouters
ABSTRACT: The CEACAM5 gene product [carcinoembryonic antigen (CEA)] is an attractive target for colorectal cancer because of its high expression in virtually all colorectal tumors and limited expression in most healthy adult tissues. However, highly active CEA-directed investigational therapeutics have been reported to be toxic, causing severe colitis because CEA is expressed on normal gut epithelial cells. Here, we developed a strategy to address this toxicity problem: the Tmod dual-signal integrator. CEA Tmod cells use two receptors: a chimeric antigen receptor (CAR) activated by CEA and a leukocyte Ig-like receptor 1 (LIR-1)-based inhibitory receptor triggered by human leukocyte antigen (HLA)-A*02. CEA Tmod cells exploit instances of HLA heterozygous gene loss in tumors to protect the patient from on-target, off-tumor toxicity. CEA Tmod cells potently killed CEA-expressing tumor cells in vitro and in vivo. But in contrast to a traditional CEA-specific T cell receptor transgenic T cell, Tmod cells were highly selective for tumor cells even when mixed with HLA-A*02-expressing cells. These data support further development of the CEA Tmod construct as a therapeutic candidate for colorectal cancer.
Author Info: (1) Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 91301, USA. (2) Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills,
Author Info: (1) Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 91301, USA. (2) Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 91301, USA. (3) Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 91301, USA. (4) Process Development, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 91301, USA. (5) Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 91301, USA. (6) Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 91301, USA. (7) Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 91301, USA. (8) Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 91301, USA. (9) Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 91301, USA. (10) (11) Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 91301, USA. (12) Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 91301, USA. (13) Process Development, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 91301, USA. (14) Process Development, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 91301, USA. (15) Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 91301, USA. (16) Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 91301, USA. (17) Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 91301, USA.
