Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors

Abstract

Chimeric antigen receptors (CARs) are synthetic receptors that target T cells to cell-surface antigens and augment T-cell function and persistence. Mesothelin is a cell-surface antigen implicated in tumor invasion, which is highly expressed in mesothelioma, lung, pancreas, breast, ovarian, and other cancers. Its low-level expression in mesothelia however commands thoughtful therapeutic interventions. Encouragingly, recent clinical trials evaluating active immunization or immune-conjugates in patients with pancreatic adenocarcinoma or mesothelioma have shown responses without toxicity. Altogether, these findings and preclinical CAR therapy models using either systemic or regional T-cell delivery argue favorably for mesothelin CAR therapy in multiple solid tumors.

A new anti-mesothelin antibody targets selectively the membrane-associated form

“…53 In addition, studies on genetically modified T cells with CARs, including anti-mesothelin CAR T cells, report significant efficacy in different malignancies. 54,55 This membrane-bound antigen specificity could be of interest for generating anti-mesothelin CAR T cells using one of these discriminating Fabs.…”

New horizons from immunotherapy in malignant pleural mesothelioma

“…In phase I studies, SS1P generated neutralizing antibodies to the pseudomonas endotoxin (PE) (51,52); therefore, in a subsequent study, pentostatin and cyclophosphamide were given before the administration of SS1P to deplete T and B lymphocyte, thus delaying the A phase I study to assess the maximum tolerated dose and the immunogenicity of RG778 is currently under way in MPM patients (NCT02798536). (IV) Mesothelin CARs: adoptive T cell therapy using engineered T cells directed towards tumor antigens (CAR-T) is another promising approach that has shown impressive clinical outcomes in leukemia, and it is now being investigated in solid malignancies (55). Mesothelin is an especially appealing target for this approach since it is overexpressed in the majority of MPM, and several preclinical and clinical studies have found that is involved in tumorigenesis, as well as being associated with tumor aggressiveness (56).…”

Advances in cancer immunology and cancer immunotherapeutics

“…[84] Efforts to identify highly specific tumor antigen is required to minimize the on target-off tumor effects. [85] At present, TCR therapy against NY-ESO antigen for advanced synovial sarcoma in LA-A*201, HLA-A*205, or HLA-A*206 allele-positive patients has been granted breakthrough therapy designation by the FDA. [86,87] …”