Advancements in Mesothelin-Targeted CAR T Cell Therapy: From Preclinical to Phase I Clinical Trial

The study builds upon previous work that confirmed the safety and antitumor effects of mesothelin-targeted CAR T cells combined with a PD-1 antibody. Researchers have now developed an improved version of CAR T cells, which includes a modified signaling domain and a PD-1 dominant negative receptor to enhance their antitumor capabilities. Preclinical data show that these new CAR T cells have increased safety and efficacy.

In the methods section, the researchers compared the cytotoxicity, proliferation, and cytokine production of human T cells engineered with the original and the new CAR T cells. They also tested the in vivo antitumor effects of these cells in mice with pleural mesothelioma, using bioluminescence imaging and survival analysis.

Results indicate that both types of CAR T cells showed specific cytotoxicity and cytokine secretion in vitro, but the new CAR T cells were more effective in eradicating tumors and enhancing survival in mice. Additionally, the new CAR T cells demonstrated resistance to tumor reestablishment upon repeated challenges.

A table in the results section details the characteristics of both CAR T-cell constructs, including target specificity, costimulatory domain, and mutations in the CD3z domain. It also presents in vitro and in vivo results, such as transduction range, cytotoxicity, accumulation, and cytokine levels, as well as tumor eradication times and survival data.

The conclusion highlights that due to their safety, effectiveness in eliminating tumors, and persistence, the new CAR T cells are poised for IND submission and a phase I clinical trial for patients with pleural mesothelioma. The findings also suggest potential for further investigation into other solid tumors that express mesothelin.

The citation information is provided, indicating the study's presentation at the Annual Meeting of the American Association for Cancer Research in 2020.