Prasad S. Adusumilli, MD

Prasad S. Adusumilli, MD, surgeon, deputy chief of Thoracic Service, co-director of the Mesothelioma Program, head of Solid Tumors Cell Therapy, Cellular Therapeutics Center, at Memorial Sloan Kettering Cancer Center, discusses the rationale for an autologous mesothelin-targeted CAR T-cell therapy in advanced solid tumors.

Surface antigens, such as CD19, are more easily targeted in hematologic malignancies than they are in solid tumors, explains Adusumilli. Prior to the phase I study that investigated the use of an autologous mesothelin-targeted CAR T-cell therapy, investigators studied approximately 2,000 thoracic cancers and noticed that mesothelin is overexpressed in mesothelioma, lung cancer, triple-negative breast cancer, and pancreatic cancer.

Most importantly, investigators realized that mesothelin was partially responsible for the aggressiveness of the disease, making it unlikely that the cancer cell will shed the antigen under immune attack. They realized that if they were able to target mesothelin, approximately 2,000,000 patients could be treated in the United States alone, says Adusumilli. Moreover, they learned that by targeting mesothelin, they could target the tumor cells and spare the patient’s normal cells.

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Dr. Adusumilli on the Rationale for Mesothelin-Targeted CAR T-Cell Therapy

Prasad S. Adusumilli, MD, surgeon, deputy chief of Thoracic Service, co-director of the Mesothelioma Program, head of Solid Tumors Cell Therapy, Cellular Therapeutics Center, at Memorial Sloan Kettering Cancer Center, discussed the results of a phase I study exploring mesothelin-targeted CAR T-cell therapy in patients with advanced solid tumors during the 2019 AACR Annual Meeting.

Results from the phase I clinical trial (NCT02414269) showed that the CAR T-cell therapy had antitumor activity in patients with malignant pleural disease from mesothelioma without any evidence of major toxicity.

There is a lot of concern regarding on-target off-tumor toxicity, says Adusumilli. However, if there had been any unexpected toxicities, the therapy was designed with completely human components, including an Icaspase-9 safety “suicide” switch. If initiated, all CAR T cells in the patient’s body would be eliminated. Adusumilli and his team used clinical laboratory imaging to look for this kind of toxicity and they did not find it following extensive investigation, he says.

Due to the lack of toxicity, investigators added checkpoint blockade to patients who had been given a single dose of CAR T cells intrapleurally, and they noticed durable responses. These responses lasted for ≥6 months without the need of additional therapies, says Adusumilli.

The next step for research is to find a way to allow for patients to stop treatment eventually instead of having to receive anti—PD-1 therapy every 3 weeks for the remainder of their lives. To this end, Adusumilli and his team have genetically engineered a PD-1 dominant negative receptor. This is essentially a decoy receptor that can be placed within the CAR, thus the T cell can then bind to PD-L1 without exhausting the CAR T cell through intracellular signaling. This clinical trial is slated to launch in 2020.

Prasad S. Adusumilli, MD

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Dr. Adusumilli on the Rationale for Mesothelin-Targeted CAR T-Cell Therapy

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