Anti-Mesothelin CAR T cell therapy for malignant mesothelioma

Abstract

Malignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a novel potential treatment for this incurable solid tumor. The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in MM, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of MM patients and not (or very modestly) present in healthy tissues. Clinical trials using anti-MSLN CAR T cells in MM have shown that this potential therapeutic is relatively safe. However, efficacy remains modest, likely due to the MM tumor microenvironment (TME), which creates strong immunosuppressive conditions and thus reduces anti-MSLN CAR T cell tumor infiltration, efficacy and persistence. Various approaches to overcome these challenges are reviewed here. They include local (intratumoral) delivery of anti-MSLN CAR T cells, improved CAR design and co-stimulation, and measures to avoid T cell exhaustion. Combination therapies with checkpoint inhibitors as well as oncolytic viruses are also discussed. Preclinical studies have confirmed that increased efficacy of anti-MSLN CAR T cells is within reach and offer hope that this form of cellular immunotherapy may soon improve the prognosis of MM patients.

Mesothelin-Specific CAR T Cells Target Ovarian Cancer

“…Earlier reports showing antitumor activity and improved survival in subcutaneous and intraperitoneal preclinical models raised CAR T-cell therapy to a promising treatment modality for those patients (20,21). Furthermore, clinical trials using MSLN-directed CAR T cells have so far demonstrated no on-tumor/off-target toxicity (22)(23)(24)). Yet, phase I studies using MSLN-targeted CAR T cells with murine-derived scFv in patients with solid tumors showed potential but limited effect (25,26).…”

Dual-targeting CAR-T cells with optimal co-stimulation and metabolic fitness enhance antitumor activity and prevent escape in solid tumors

“…Here, we propose an approach based on dual targeting, split costimulatory signaling and shared CD3ζ chain tailored to target two clinically relevant antigens -GD2 and B7-H3in the disease model of neuroblastoma (NB) [19][20][21] , and further validated the approach with an additional pair of targets, mesothelin (MSLN) and chondroitin sulphate proteoglycan 4 (CSPG4) [22][23][24] . We demonstrated that the designed strategy allows achieving rapid and sustained antitumor effects, which are sustained by optimized signaling, effector molecular signature and metabolic fitness of the CAR-T cells.…”

Hitting the Bull’s-Eye: Mesothelin’s Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma

“…Adoptive cell therapy targeting MSLN has emerged as a potential therapy for the treatment of MPM with numerous clinical trials [129]. Chimeric Antigen Receptor (CAR) T cellular immunotherapy entails genetically engineering T cells to target the tumor.…”

“…Overall, the results of MSLN-directed CAR T cell therapy are encouraging, with manageable toxicity and no reported 'on-target/off-tumor' effects. Novel strategies to improve CAR T cell efficacy are currently being tested in clinical trials, with many more in the preclinical stage [129]. Furthermore, allogeneic 'off the shelf' MSLN-targeted CAR T cells are being developed.…”