By Prasad S. Adusumilli, MD, FACS, FCCP
Posted: November 12, 2019
My colleagues and I conducted a phase I clinical trial of mesothelin-targeted chimeric antigen receptor (CAR) T-cell therapy in patients with malignant pleural disease from mesothelioma and metastatic lung or breast cancer, and we presented the findings at the 2019 American Association for Cancer Research Annual Meeting.1 Following cyclophosphamide preconditioning, patients were administered a single, escalating dose of mesothelin-targeted CAR T cells intrapleurally via catheter or by interventional radiologic procedures. The primary observation was that this therapy is safe and effective, especially when combined with anti–PD-1 agents following CAR T-cell administration.
IcasM28z CAR T cells were administered directly into the pleural cavity in 21 patients with malignant pleural disease (19 with malignant pleural mesothelioma, one with metastatic lung cancer, and one with metastatic breast cancer). These T cells included Icaspase-9, a safety gene that can be switched on in case of an unexpected toxicity.
During the follow-up period, the IcasM28z CAR T cells were found to be persistent in the peripheral blood of patients, which was associated with reduction in the levels of serum meso-thelin–related peptide levels and evidence of tumor regression on imaging studies. On the basis of the rationale from our preclinical studies, 14 patients went on to receive anti–PD-1 checkpoint blockade agents. Among 11 patients who had at least 3 months of follow-up, 2 patients had complete metabolic response on PET scans at 60 and 32 weeks, respectively, and one response ongoing at the time of reporting; 5 patients had partial response, and 4 had stable disease.
Study Rationale and Future Directions
In our initial explorations for a cancerassociated antigen with high expression in solid tumors and very low expression in normal tissues, we observed that mesothelin is expressed in a majority of solid tumors—approximately 2 million tumors in the United States per year. The very low expression of mesothelin in normal tissues compared with cancer tissue, indicated the safety margin of targeting mesothelin. Our investigations in thoracic tumors and in preclinical mouse models showed that mesothelin overexpression affects tumor aggressiveness. This suggested that cancer cells are unlikely to shed mesothelin as an antigen immune-escape mechanism. These characteristics—relatively higher expression in cancer than in normal tissue, expression in a large number of patients with solid tumors, and evidence that cancer cells need mesothelin expression for their aggressiveness— rationalized the selection of mesothelin as an antigen target.
Because solid tumors notoriously inactivate tumor-infiltrating lymphocytes and further render infiltrating lymphocytes ineffective by immunosuppressive mechanisms such as the PD-L1/ PD-1 pathway, our strategies were designed to counteract these known factors. We studied and published findings on the tumor immune microenvironments of more than 2,000 solid tumors in patients with thoracic cancer, primarily mesothelioma and metastatic lung and breast cancers. Understanding the tumor microenvironment helped us design effective CAR T cells by use of genetic engineering. We designed the CAR to be effective against cancer cells but to spare normal cells, and we armored the CAR with potent CD28 costimulation without the need for help from other immune cells. Our CAR is the first in the world to be developed from all human genetic components so that a patient’s immune system will not reject the CAR T cells in the long term, and we were able to help overcome tumor-induced immunosuppression by administering checkpoint blockade agents following CAR T cells.
More importantly, because our clinically relevant mouse models showed that CAR T cells infused through blood are sequestered in the lungs for a few days and are not able to enter the tumor efficiently, we investigated and translated the previously mentioned strategy of directly injecting CAR T cells intrapleurally, thereby avoiding toxicity and increasing efficacy by several fold. This approach is the first in the world of its kind.
We plan to continue combination therapy with mesothelin-targeted CAR T cells and anti–PD-1 agents with dose escalation and administration of anti– PD-1 agents 4 weeks after CAR T cells. To further make the above strategy tumor specific, we designed a “decoy receptor”: a PD-1 dominant negative receptor (DNR) that is combined with mesothelin-targeted CAR. We are now conducting Investigational New Drug studies to translate mesothelin PD DNR CAR into a clinical trial by early 2020.
In our publication, we have shown that at least 2 million patients with solid tumors in the United States alone are eligible for this therapy. Among solid tumors, the mesothelin antigen that we are targeting is expressed in mesothelioma (90%), lung cancer (60%), triplenegative breast cancer (35%), pancreatic cancer (70%), and ovarian cancer (60%), as well as stomach, colon, and other cancers. ✦
About the Author: Dr. Adusumilli is deputy chief and attending, Thoracic Service, Department of Surgery; Head, Solid Tumors Cell Therapy, Cellular Therapeutics Center; Director, Mesothelioma Program; and Vice Chair for Translation Research, Department of Surgery at Memorial Sloan-Kettering Cancer Center.
1. Adusumilli PS, Zauderer MG, Rusch V, et al. A phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR T cells: Safety and efficacy. Paper presented at: 2019 AACR Annual Meeting: March 29-April 3, 2019; Atlanta, GA.