|The following article features coverage from the IASLC 2019 World Conference on Lung Cancer meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.|
Results of preclinical studies showed that exposure of lung adenocarcinoma cell lines to mesothelin-directed chimeric antigen receptor (CAR) T-cell (CAR-T) therapy resulted in a level of cell lysis proportional to the cellular expression of mesothelin. The findings of this study were presented at the IASLC 2019 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer held in Barcelona, Spain.
Mesothelin is a tumor-associated antigen that is highly expressed in several human cancers, including malignant mesothelioma and lung adenocarcinomas. Although mesothelin is also expressed on normal mesothelial cells that line the pleura, pericardium, and peritoneum, those cells are not considered indispensable. Hence, mesothelin represents an attractive target for tumor antigen-directed therapy. In this study, the feasibility of using CAR-T therapy directed against mesothelin in patients with advanced lung adenocarcinoma was investigated.
Tumor specimens from patients with stage I to stage III lung adenocarcinoma (1438 patients) were stained for mesothelin expression. In addition, tissue was collected from the metastatic sites of those patients with distant recurrence of disease (327 individuals), and also evaluated for expression of mesothelin.
CAR-T cells directed against mesothelin created from healthy donor cells were evaluated in different lung adenocarcinoma cell lines with varying levels of expression of mesothelin, and also in mice with large lung adenocarcinoma tumors.
Key findings from this study include a higher level of mesothelin expression in metastatic compared with matched primary tumor lesions (65% vs 38%, respectively), and in tumors characterized by a KRAS mutation compared with KRAS wild-type tumors (42% versus 32%, respectively). Furthermore, CAR-T cell cytokine secretion and tumor cell lysis was observed to be proportional to the level of mesothelin expression in lung adenocarcinoma cell lines.
Interestingly, in mice, established lung adenocarcinoma tumors with a high level of mesothelin expression were eradicated by a single dose of mesothelin-directed CAR-T therapy — and no toxicity to normal tissue observed.
The study authors concluded that “these results provide strong rationale for our upcoming MSLN-targeted CAR T cell therapy clinical trial in metastatic, KRAS-mutant lung [adenocarcinoma] patients.”
Read more of Cancer Therapy Advisor‘s coverage of the IASLC annual meeting by visiting the conference page.
Minehart JC, Eguchi T, Morello A, Adusmilli PS. Clinical rational and preclinical evidence for chimeric antigen receptor (CAR) T cell therapy clinical trial in KRAS-mutant lung cancer. Presented at: IASLC 2019 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract OA14.03.