Focused on optimizing the efficacy of TC-210, a mesothelin (MSLN)-specific TCR fusion construct (TRuC®), McCarthy et al. designed a chimeric switch receptor (CSR; PD-1 ectodomain fused to CD28 intracellular domain) to co-opt PD-1 signaling with CD28-mediated costimulation, resulting in enhanced TCR signaling and sustained effector function in the presence of PD-L1. The PD1TM performed better than the CD28TM. Anti-MSLN TRuC-T cells with PD1-CD28 CSR (TC-510) were superior in vitro and in vivo compared to TC-210, and showed significantly improved persistence and effector functions, resistance to exhaustion, and prolonged antitumor efficacy after rechallenge.
Contributed by Katherine Turner
ABSTRACT: T cells expressing a mesothelin (MSLN)-specific T cell receptor fusion construct (TRuC®), called TC-210, have demonstrated robust antitumor activity in preclinical models of mesothelioma, ovarian cancer, and lung cancer. However, they are susceptible to suppression by the programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) axis and lack intrinsic costimulatory signaling elements. To enhance the function of anti-MSLN TRuC-T cells, chimeric switch receptors (CSRs) have been designed to co-opt the immunosuppressive PD-1/PD-L1 axis and to deliver a CD28-mediated costimulatory signal. Here, we report that coexpression of the PD1-CD28 CSR in TRuC-T cells enhanced T cell receptor signaling, increased proinflammatory effector cytokines, decreased anti-inflammatory cytokines, and sustained effector function in the presence of PD-L1 when compared with TC-210. Anti-MSLN TRuC-T cells engineered to coexpress PD1-CD28 CSRs comprising the ectodomain of PD-1 and the intracellular domain of CD28 linked by the transmembrane domain of PD-1 were selected for integration into an anti-MSLN TRuC-T cell therapy product called TC-510. In vitro, TC-510 showed significant improvements in persistence and resistance to exhaustion upon chronic stimulation by tumor cells expressing MSLN and PD-L1 when compared with TC-210. In vivo, TC-510 showed a superior ability to provide durable protection following tumor rechallenge, versus TC-210. These data demonstrate that integration of a PD1-CD28 CSR into TRuC-T cells improves effector function, resistance to exhaustion, and prolongs persistence. Based on these findings, TC-510 is currently being evaluated in patients with MSLN-expressing solid tumors.
Author Info: (1) TCR2 Therapeutics, Inc., 100 Binney Street, Suite 710, Cambridge, MA, 02142, USA. (2) Adaptimmune, Philadelphia, PA, USA. (3) Adaptimmune, Philadelphia, PA, USA. (4) TCR2 Thera
Author Info: (1) TCR2 Therapeutics, Inc., 100 Binney Street, Suite 710, Cambridge, MA, 02142, USA. (2) Adaptimmune, Philadelphia, PA, USA. (3) Adaptimmune, Philadelphia, PA, USA. (4) TCR2 Therapeutics, Inc., 100 Binney Street, Suite 710, Cambridge, MA, 02142, USA. (5) TCR2 Therapeutics, Inc., 100 Binney Street, Suite 710, Cambridge, MA, 02142, USA. (6) TCR2 Therapeutics, Inc., 100 Binney Street, Suite 710, Cambridge, MA, 02142, USA. (7) Center of Integrated Protein Science Munich (CIPS_M) and Division of Clinical Pharmacology, Department of Medicine IV, Member of the German Center for Lung Research (DZL), University Hospital, Ludwig-Maximilians-Universitt, Munich, Germany. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. (8) TCR2 Therapeutics, Inc., 100 Binney Street, Suite 710, Cambridge, MA, 02142, USA. Institute of Immunology, Ludwig-Maximilians-Universitt, Munich, Germany. (9) TCR2 Therapeutics, Inc., 100 Binney Street, Suite 710, Cambridge, MA, 02142, USA. (10) TCR2 Therapeutics, Inc., 100 Binney Street, Suite 710, Cambridge, MA, 02142, USA. (11) TCR2 Therapeutics, Inc., 100 Binney Street, Suite 710, Cambridge, MA, 02142, USA. rob.tighe1973@gmail.com.
