Results from an ongoing phase 1 clinical trial1 using chimeric antigen receptor (CAR) T cells (CAR-T) in pleural cancers were presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting (ClinicalTrials.gov Identifier: NCT02414269). The study featured preliminary results from 27 patients, 25 of whom had mesothelioma. The other 2 had metastatic solid tumors of the lung or breast that had spread to the pleura.
All of the patients on the trial had a minimum of 3 previous treatment cycles with conventional therapies. For mesothelioma, there are currently no curative treatment options in existence, and the standard treatments to attempt to prolong life come with considerable impact on quality of life.
“There are many different types of mesothelioma. The best response is 9-17 months with combination chemotherapy, radiation and an extensive surgical procedure, but for some types there is no treatment and people are expected to live [fewer] than 6 months postdiagnosis,” said Prasad Adusumilli, MD, lead author of the research and codirector of the Mesothelioma Program at Memorial Sloan Kettering Cancer Center, New York, New York.
The CAR T cells in this trial were designed to target a protein called mesothelin, found on a range of tumor types, including typically hard-to-treat cancers such as lung and pancreatic cancers, as well as the pleural cancers that were the focus of this study. Before receiving CAR-T therapy, 24 of the patients in the cohort were given cyclophosphamide preconditioning, but the first 3 patients in the trial who received CAR-T did not get cyclophosphamide as a result of prior concerns about toxicity.
“Some cohorts didn’t receive cyclophosphamide initially, as we feared that this could have increased toxicity at first — but this didn’t happen, and we now know that CAR T cells work much better with preconditioning with cyclophosphamide,” said Dr Adusumilli.
In addition to this, following promising results in mice, the trial also tested adding anti–PD-1 therapy pembrolizumab, 6 weeks to 8 weeks postadministration of CAR-T, finding that it prolonged the activity of the therapy.
“We noticed that the CAR T cells went to the cancer, killed cells, but get exhausted by PD-1. PD-1 inhibition keeps CAR T cells going,” said Dr Adusumilli.
Of the patients who received cyclophosphamide, CAR-T therapy, and at least 3 doses of anti–PD-1 (with a minimum 3 months follow-up), 63% of patients achieved either a partial response or a complete response. Additionally, in these 16 patients, the engineered cells persisted in the pleural fluid for up to 42 weeks.
The target of the CAR-T, mesothelin, is also expressed on healthy tissues such as the heart, lung and abdominal cavity, raising initial concerns that the treatment strategy could be impeded by high toxicity. However, the results presented showed patients experienced only minimal, manageable toxicities from treatment with the adoptive cell therapies, critically, with no cytokine release syndrome (CRS) or neurotoxic effects, which were serious adverse events that plagued early CAR-T trials.
“I was impressed by these results, because mesothelin-targeted trials have been tested before and the results have been a little underwhelming, so the fact we can see a clinical response in this case with minimal toxicity, this is remarkable,” said Daniel Abate-Daga, PhD, assistant member of the department of immunology at Moffit Cancer Center and assistant professor in the department of oncological sciences at the University of South Florida, Tampa.