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.