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Speaker: Rationale exists to test CAR T-cell therapy in KRAS-mutated lung cancer
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BARCELONA — Enriched cell surface expression of mesothelin in KRAS-mutated adenocarcinoma and supporting preclinical evidence suggest chimeric antigen receptor T-cell therapy targeting mesothelin may be feasible and efficacious for this group of patients, according to a presentation at International Association for the Study of Lung Cancer World Conference on Lung Cancer.
“KRAS mutation is the most common oncogenic driver mutation in lung adenocarcinoma and is associated with poor prognosis,” Janna Minehart, medical student at New York University School of Medicine and research fellow at Memorial Sloan Kettering Cancer Center, said during her presentation. “Despite extensive efforts, there is no targeted therapy currently available for [these patients]. There is some suggestion that KRAS mutations are associated with better response to checkpoint blockade, potentially because of their higher tumor mutational burden, but response rates to checkpoint blockade are still limited.”
Minehart and colleagues sought to evaluate whether they could improve antitumor immune activity and responses to immunotherapy using CAR T-cell therapy.
In a previous phase 1 report, researchers evaluated a single dose of CAR T-cell therapy followed by checkpoint blockade among 14 patients with malignant pleural mesothelioma. Results showed two patients achieve complete response, five achieved partial response and four had stable disease.
“Although CAR T cells have had a ton of success in hematologic malignancies, solid tumors present additional challenges,” Minehart said. “Some of our considerations, as we are designing a trial, include identifying a safe and appropriate antigen to target, how antigen heterogeneity might impact efficacy, and how to overcome tumor-mediated immunosuppression.”
Researchers focused on mesothelin, a tumor-associated antigen that is overexpressed on mesothelioma, lung cancer and other solid tumors.
“One important characteristic of a tumor-associated antigen to target is that it has low-level expression on normal tissues to avoid on-target, off-tumor toxicity,” Minehart said. “Mesothelin is expressed at low levels restricted to the pleura, pericardium and peritoneum.”
Research has shown that mesothelin expression is associated with poor survival and KRAS mutations.
A targetable tumor-associated antigen also needs to be expressed on the cell surface so it is accessible to the CAR, Minehart said.
Tissue microarray studies from 1,438 patients with stage I to stage III lung adenocarcinoma showed mesothelin expression on the cell surface and cytoplasm. Further, as the cancer stage increased, so did mesothelin cell surface expression.
Mesothelin cell surface expression also was more common among tumors with KRAS mutations (42% vs. 32%), and researchers found that metastatic sites had greater mesothelin expression than the autologous primary matched tumor (65% vs. 38%).
Cell lines showed that CAR T cells release more cytokines in response to mesothelin-high targets with greater cytotoxicity when co-cultured with mesothelin-high targets.
In vivo analyses also showed that one dose of CAR T cells eradicated primary and metastatic mesothelin-high tumors without off-tumor toxicity.
Because addressing antigen heterogeneity is important to move these analyses further, Minehart and colleagues are evaluating strategies to increase cell surface mesothelin expression.
“As we know, preclinical models don’t fully recapitulate the complexity we see in patients, so we still have a lot to learn about the interplay of both CAR and antigen parameters,” Minehart said. “Case in point, we had one patient in the mesothelioma trial whose tumor was less than 50% mesothelin positive, who had a complete response after CAR T-cell therapy and checkpoint blockade, indicating there might be some component of epitope spreading promoting endogenous T-cell responses that in some circumstances may overcome antigen heterogeneity.”
Tumor-mediated immune suppression is another barrier to CAR T-cell therapy in this area. A mesothelioma model showed that when tumor cells are treated with CAR T cells, they upregulate PD-L1 and PD-L2, leading to inhibition of T-cell activity. Minehart and colleagues have developed a dominant negative receptor that prolongs survival of animal models by rescuing T cell-mediated exhaustion.
Based on their findings that cell surface mesothelin expression is common in adenocarcinoma and enriched among patients with advanced disease and KRAS mutations, researchers are developing a phase 1 trial to assess mesothelin CAR T-cell therapy plus checkpoint blockade in advanced non-small cell lung cancer. – by Alexandra Todak
Reference:
Minehart J, et al. Abstract OA14.03. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer; Sept. 7-10, 2019; Barcelona.
Disclosures: Minehart reports that this research was supported by the Doris Duke Charitable Foundation, and that mesothelin CAR is licensed by a biotech company. Please see the abstract for all other authors’ relevant financial disclosures.