Anti-Mesothelin CAR T cell therapy for malignant mesothelioma

Our plain-English summary of Anti-Mesothelin CAR T cell therapy for malignant mesothelioma, by L. Castelletti, D. Yeo, N. van Zandwijk, et al (Biomarker Research, 2021).

The study

• Authors: L. Castelletti, D. Yeo, N. van Zandwijk, J.E.J. Rasko
• Journal: Biomarker Research
• Published: 2021;9(1):11
• Type of article: Review
• Cited by: 84 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a review article on anti-mesothelin (MSLN) chimeric antigen receptor (CAR) T cell therapy for malignant mesothelioma, a tumour of the pleural or abdominal mesothelial lining that the authors described as often elicited by prior asbestos exposure. The authors summarised clinical trials sourced from Clinicaltrials.gov in October 2020, together with preclinical work on CAR design and the tumour microenvironment. Among reported trial results, a National Cancer Institute trial was terminated for insufficient accrual, with 1 of 15 patients showing stable disease; a University of Pennsylvania mRNA CAR trial reported a transient tumour response in 2 of 18 patients and one severe anaphylactic reaction attributed to antibodies against the murine CAR; a lentiviral CAR trial reported stable disease in 11 of 15 patients at day 28, with 5 later progressing; a MaxCyte intraperitoneal trial reported 4 of 11 patients with initial stable disease; and a Memorial Sloan Kettering intrapleural trial reported, among 19 malignant pleural mesothelioma patients (13 given pembrolizumab), two complete metabolic responses, 5 partial responses and 4 with stable disease. The authors concluded that trials show manageable toxicity but that response rates have remained low.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: narrative review of clinical trials and preclinical studies
• Who was studied: Published and reported trials of anti-mesothelin CAR T cell therapy in malignant mesothelioma and other mesothelin-expressing tumours, identified from Clinicaltrials.gov in October 2020, plus preclinical mouse and in vitro studies
• Exposure: Anti-mesothelin CAR T cell therapy (various CAR constructs, mRNA or lentiviral transduction, systemic, intrapleural or intraperitoneal delivery), sometimes with lymphodepletion or checkpoint inhibitors; mesothelioma itself attributed largely to prior asbestos exposure
• Main results:
  • National Cancer Institute trial (NCT01583686, SS1 scFv CAR, systemic): terminated after 6 years for insufficient accrual; safety manageable but only 1 of 15 patients had stable disease
  • University of Pennsylvania mRNA anti-MSLN CAR trial (NCT01355965, MPM and pancreatic ductal adenocarcinoma): one MPM patient had severe anaphylaxis after a third infusion; transient tumour response in 2 of 18 patients
  • University of Pennsylvania mRNA CAR trial response: transient response in 2 of 18 patients
  • Lentivirally transduced anti-MSLN CAR trial (NCT02159716, 15 patients with MPM, PDAC and ovarian cancer): low persistence and low tumour infiltration; best overall response stable disease in 11 of 15 patients at day 28, 5 of whom later progressed
  • MaxCyte intraperitoneal MCY-M11 trial (NCT03608618, preliminary ASCO 2020 results): treatment well tolerated, 4 of 11 patients with initial stable disease, maintained in 3 patients for more than two months
  • Memorial Sloan Kettering intrapleural iCasp9M28z trial (NCT02414269, preliminary AACR/ASCO 2019 results) in 19 MPM patients, 13 of whom received pembrolizumab: two complete metabolic responses, 5 partial responses, 4 stable disease, no on-target/off-tumour toxicities
  • TCR2 Therapeutics TC-210 TRuC trial (NCT03907852): preliminary results in 5 patients (4 with MM, 1 with ovarian cancer) showed manageable toxicity and some tumour shrinkage
  • Preclinical: intrapleural delivery required a 30-fold lower dose of anti-MSLN CAR T cells than intravenous injection for tumour eradication
• The authors' conclusion: The authors concluded that, despite limited response rates in mesothelioma trials so far, anti-MSLN CAR T cell therapy represents a promising treatment modality, with MSLN shown to be a specific and safe target and ongoing work on CAR design and combinations increasing infiltration, efficacy and persistence
• Limitations the authors state:
  • The authors stated it is too early to determine which approach works best, that most trials are phase I or I/II with safety as the primary endpoint, and that response rates remained low
  • The authors noted efficacy was not the primary endpoint of the listed trials and CAR T cell dosage still needs optimisation
  • The authors stated further research is needed on the antitumour benefit of lymphodepletion and on which costimulatory domains give better clinical response

Topics

Medical terms in this study, explained in our Lexicon: Mesothelin, Mesothelioma, Pleura, Prognosis, Peritoneum, Clinical Trial, Tumor Microenvironment, checkpoint inhibitors.

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