CAR T cell therapy in lung adenocarcinoma may be beneficial, but still early days

A new approach in solid cancer is the use of chimeric antigen receptor (CAR) T cells. These cells are engineered to express a synthetic receptor that redirects specificity to a tumour-associated antigen. Mesothelin is a tumour-associated antigen expressed by solid tumours, notably in mesothelioma and lung adenocarcinoma. Previous research of mesothelin-targeted CAR T cells in mesothelioma demonstrated a favourable safety profile as well as evidence of antitumor activity. This led to the evaluation of the feasibility and utility of mesothelin-targeted CAR T cell therapy in advanced, KRAS-mutant lung adenocarcinoma.

In the study by Minehart et al., 2 pathologists reviewed tissue microarray from stage I-III resected lung adenocarcinomas (n=1,438), which was subsequently stained for mesothelin expression on cell-surface and cytoplasm. Of a total of 327 patients with distant recurrences, adequate tissue was available from 34 autologous metastatic sites for evaluation of mesothelin expression. Healthy donor T cells were retrovirally transduced with a mesothelin-targeted CAR. In vitro function against lung adenocarcinoma cell lines with heterogenous mesothelin expression resembling human tumours was assessed via chromium release assay, ELISA, and flow cytometry. In vivo antitumor efficacy (n=30) was evaluated by median survival and tumour bioluminescence in mice bearing lung adenocarcinoma tumours [1].

It was found that the incidence of cell-surface mesothelin expression was higher in metastases than matched primary tumours (65% vs 38%) and higher in KRAS-mutant than wild type tumours (42% vs 32%). CAR T cells secreted cytokines and lysed lung adenocarcinoma cell lines in proportion to their cell-surface mesothelin expression. No activity against mesothelin-very low mesothelial or mesothelin-negative lung adenocarcinoma cell lines was observed. In vivo, a single dose of CAR T cells eradicated established primary and metastatic mesothelin-high tumours without evidence of on-target off-tumour toxicity.

Researchers concluded that therapeutically relevant cell surface mesothelin expression is enriched in a population of KRAS-mutant lung adenocarcinoma patients who have a poor prognosis and limited treatment options. Mesothelin-targeted CAR T cells appear safe and effective against lung adenocarcinoma, both in vitro and in vivo. Therefore, it was put forward that these results provide a strong rationale for the upcoming mesothelin-targeted CAR T cell therapy clinical trial in metastatic, KRAS-mutant lung adenocarcinoma patients. However, during the discussion afterwards, it was stated that although the results of this CAR T cell therapy in lung cancer are interesting, they are still quite premature, which highlights the need for more and larger studies [1].

1. Minehart J, et al. OA14.03 WCLC 2019.

Posted on 8 November 20195 March 2021