Functional enhancement of mesothelin-targeted TRuC-T cells by a PD1-CD28 chimeric switch receptor

• Published in: Cancer Immunology, Immunotherapy Vol. 72; no. 12; pp. 4195 - 4207
• Main Authors: McCarthy, Derrick, Lofgren, Michael, Watt, Amy, Horton, Holly, Kieffer-Kwon, Philippe, Ding, Jian, Kobold, Sebastian, Baeuerle, Patrick A., Hofmeister, Robert, Gutierrez, Dario A., Tighe, Robert
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-12-2023; Springer Nature B.V
• Subjects: Antitumor activity; Apoptosis; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Cancer Research; CD28 antigen; CD28 Antigens; Cell death; Cell fusion; Cell therapy; Cytokines; Cytokines - metabolism; Effector cells; Humans; Immunology; Inflammation; Lung cancer; Lymphocytes; Lymphocytes T; Medicine; Medicine & Public Health; Mesothelin; Mesothelioma; Oncology; Ovarian cancer; PD-1 protein; PD-L1 protein; Programmed Cell Death 1 Receptor - metabolism; Receptor mechanisms; Receptors, Antigen, T-Cell - metabolism; Solid tumors; T cell receptors; T-Lymphocytes - metabolism; Tumor cells; Mesothelin; PD-L1; CD28; Solid tumor; T cell receptor fusion construct T cells; PD-1
• ISSN: 0340-7004; 1432-0851; 1432-0851
• DOI: 10.1007/s00262-023-03556-7

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.