Researchers from Memorial Sloan Kettering Cancer Center (MSK) have shown early promising results in using a chimeric antigen receptor (CAR) T cell therapy that targets the protein mesothelin, which is expressed on the surface of cancer cells in patients with diseases of the chest cavity — namely malignant pleural mesothelioma but also metastatic lung and breast cancer. The results from a phase I clinical trial were presented as part of the press program at the American Association for Cancer Research (AACR) Annual Meeting 2019. The findings showed tumor reduction in patients who participated in the study and no evidence of toxicity.
“Traditionally, these patients with advanced-stage solid tumors have had poor outcomes despite aggressive treatment,” said Prasad S. Adusumilli, MD, Deputy Chief of the Thoracic Service at MSK and lead author of the study. “We’ve seen great results in the treatment of blood cancers using CAR T cell therapy but have yet to see the same outcomes in treating solid tumors. These results are encouraging for patients who have limited treatment options.”
The study followed 21 patients with malignant disease in the chest cavity (19 with malignant pleural mesothelioma, one with metastatic lung cancer, and one with metastatic breast cancer). The investigators found no evidence of toxicity in any of the patients. A single dose of CAR T cells was administered directly into the chest cavity. Thirteen patients showed the presence of CAR T cells in their blood for several months, indicating signs of antitumor activity. The CAR T cells’ presence was associated with a decrease in the level of a tumor marker (a mesothelin-related peptide in the blood) and evidence of tumor regression on imaging studies.
One patient with mesothelioma underwent curative-intent surgery followed by radiation therapy to the chest. “Twenty months from diagnosis, the patient is doing well, with no further treatment,” Dr. Adusumilli noted.
Based on preclinical studies conducted in Dr. Adusumilli’s laboratory, some patients in the trial also received anti-PD-1 checkpoint blockade agents after the research team noted that in large tumors, the small dose of CAR T cells administered became functionally exhausted. The preclinical studies indicated that the introduction of anti-PD-1 agents could reactivate the exhausted CAR T cells and eradicate the tumors. Fourteen patients in the trial were administered anti-PD-1 agents off protocol as the next line of therapy. Two patients had a complete metabolic response at 38 and 60 weeks after the addition of the checkpoint blockade. Five patients had a partial response, and four had stable disease.
Dr. Adusumilli, along with Michel Sadelain, MD, PhD, who is the senior author of the study, and other researchers at MSK engineered mesothelin-targeted CAR T cells that included a “suicide” switch, which can be activated to kill all CAR T cells in a patient’s body in case of an unexpected toxicity. CAR T cells were injected directly into the chest cavity using an interventional radiology procedure. If this approach is successful, Dr. Adusumilli estimated that every year two million US patients with mesothelin-expressing solid tumors would be eligible for the treatment.
While the toxicity and efficacy results of this trial are promising, Dr. Adusumilli noted that the work is still in its early stages. “This is a phase I trial,” he said, “and the long-term effectiveness of this approach hasn’t been established. However, this study represents the first step toward harnessing these powerful treatment options for patients with diseases that are difficult to treat.”
MSK researchers, including Dr. Sadelain, have led the effort to develop immune-based treatments for cancer. MSK has been at the epicenter of discoveries in the field of CAR T cell therapy, and the institution’s work is bringing exciting new treatment options to people with cancer. In attempting to harness these discoveries and their efficacy in the treatment of solid tumors, Dr. Adusumilli is leading the charge into the next frontier of CAR T cell therapy research. This study from MSK represents the first successful set of data in the treatment of solid tumors using CAR T cell therapy.
Preclinical research leading to this clinical trial and the clinical trial itself are partly supported by awards from the National Cancer Institute, the US Department of Defense, an AACR–Stand Up To Cancer grant, and the Baker Street Foundation. MSK has licensed mesothelin CARs to Atara Biotherapeutics. MSK has received license fees and has the potential to receive royalties under the license. Drs. Adusumilli and Sadelain are inventors and will receive a share of the license income. Drs. Adusumilli’s and Sadelain’s labs receive sponsored research funding from Atara Biotherapeutics.
