Mesothelin-Targeted CAR T Cells Show Early Promise in Solid Tumors

Prasad S. Adusumilli, MD

The antitumor activity and tolerability with mesothelin-targeted CAR T-cell therapy in malignant pleural disease from mesothelioma has generated optimism for the approach in solid tumors, according to Prasad S. Adusumilli, MD.

Although CAR T-cell therapy has shown success in hematologic malignancies, it has yet to demonstrate the same utility in solid malignancies. By targeting mesothelin, a protein commonly expressed on cancer cells, investigators were able to show preliminary activity among patients with mesothelin-expressing solid tumors, of which there are an estimated 2 million cases per year.

Investigators accrued 21 patients with malignant pleural disease; 19 patients had mesothelioma, while 1 patient had lung cancer and the other had breast cancer. Forty percent of patients enrolled in the trial had received ≥3 prior lines of therapy.

Following cyclophosphamide preconditioning, CAR T cells were injected directly into the pleural cavity with an interventional radiology procedure.

Investigators reported CAR T-cell persistence in the peripheral blood of 13 patients during the 38-week evaluation, the presence of which was associated with a ≥50% decrease in the levels of a mesothelin-related peptide in the blood and tumor regression on imaging.

In preclinical studies, the addition of anti—PD-1 checkpoint blockade reactivated exhausted CAR T cells and rid the tumors in a subset of mice. In this study, 14 patients received subsequent anti–PD-1 checkpoint blockade. After up to 21 cycles of therapy with an anti–PD-1 agent, 2 patients experienced a complete response on PET scans at 60 and 32 weeks, respectively.

“Patients, even after a single dose of intrapleural CAR T cells given in combination with checkpoint blockade, experienced durable responses for at least 6 months to 1 year or longer,” said Adusumilli, who is senior author on the study.

Clinical, radiological, and laboratory processes did not reveal any dose-limiting toxicities. As a safeguard, the CAR T cell incorporated the Icaspase-9 safety “suicide” switch into its design, allowing for deactivation of the CAR T cells in the event of unanticipated toxicity.

Although the study will require extended follow-up, it serves as proof-of-concept that the use of CAR T-cell therapy in solid tumors is an approach that warrants further investigation.

In an interview with OncLive, Adusumilli, deputy chief, Thoracic Service, co-director, Mesothelioma Program, head, Solid Tumors Cell Therapy, Cellular Therapeutics Center, Memorial Sloan Kettering Cancer Center, shed light on the preliminary phase I data from the trial and the implications of this research.

OncLive: What are the latest advances with CAR T-cell therapy in the cancer space?

Adusumilli: Due to advances made in genetic engineering, we're able to engineer a receptor and infuse a patient’s own T cells [with CAR T-cell therapy]. This approach has shown dramatic responses in patients with leukemia and lymphoma. However, solid tumors are much more difficult to treat compared with leukemia and lymphoma. There are several obstacles and hurdles. The next phase of development [for this therapy] will be in solid tumors.

What was the rationale for a mesothelin-targeted CAR T-cell therapy?

We looked for surface antigens on the cancer cells of solid tumors. Unlike CD19, which is expressed on the surface of all [hematologic] cancer cells, there is not a single antigen that can be safely targeted in solid tumors. We studied about 2000 thoracic cancers and noticed that mesothelin is overexpressed in mesothelioma, lung cancer, triple-negative breast cancer, and pancreatic cancer. Most importantly, we noticed that mesothelin expression is importing aggressiveness to the cancer. Thereby, we hypothesized that if we can target mesothelin, we can treat at least 2 million patients in the United States alone. Moreover, we can target the tumor cells without impacting the normal cells. Further, we feel that it’s unlikely that the cancer cell will shed the antigen under immune attack.

What were the goals of the phase I trial?

Before the phase I trial, we did a study with mouse models. I'm a surgeon, so I see the tumor characteristics in the operating room. I also work closely with pathology. We developed mouse models of mesothelioma and non—small cell lung cancer. We know that when we inject the T cells intravenously, they get sequestered in the lung for 4 to 5 days and slowly trickle down to the tumor. Solid tumors are notorious for not letting the immune cells enter the tumor. We injected regionally into the chest cavity directly where the tumor is and we observed a high proliferation of T cells and better efficacy.

That's what we translated to the phase I clinical trial. We accrued patients with pleural mesothelioma, lung cancer, and breast cancer with mesothelin expression. After patients received cyclophosphamide lymphodepletion, we administered a single dose of CAR T cells into the chest cavity and monitored patients on a weekly basis for 8 weeks.

We also went back to the lab and mimicked what we did in the phase I trial in the mice. We gave mice with a large tumor burden a very low dose of CAR T cells. Then, we noticed that the CAR T cells within the tumor were exhausted, although in an overwhelming tumor burden, they expressed PD-1/PD-L1. When we gave anti—PD-1 agents, we were able to rescue the CAR T cells and restore their functional persistence. In this clinical trial, once the patients were stable for at least 6 weeks, we administered anti–PD-1 checkpoint blockade. Here, we’re seeing similar results as we saw in the mice. Of course, a long-term study will need to be conducted [to confirm these findings].

What were some of the other major takeaways from this research?

There is a lot of concern regarding on-target/off-tumor toxicity because mesothelin is expressed at very low levels in the pleura, peritoneum, and pericardium. However, we did not notice that in the 21-patient cohort I presented on at the meeting. Most importantly, because of the lack of toxicity, patients are able to return to their normal function. This gave us the idea to go ahead with the combination of CAR T cells and checkpoint blockade.

Now, patients want to know when they can stop therapy, so we genetically engineered a PD-1 receptor. It's a decoy receptor we can put within the CAR, thereby allowing the T cell to bind with PD-L1 without intracellular signaling. Therefore, the CAR T cell won't be exhausted. We plan to start that trial next year.

The rumor that CAR T-cell therapy for solid tumors is dead is premature. We have to continue to rationally build upon what we did in the last 10 years with mouse models, build safe CARs, and explore combination approaches with immunotherapy. CAR T-cell therapy has an optimistic outlook in solid tumors. Regional delivery is something that needs to be explored for patients with metastases in the liver, lung, pleural cavity, peritoneal cavity, and intracranial area. To start with regional delivery and alter the tumor microenvironment and then combine other immunotherapies is exciting as we look to the future.

Adusumilli PS, Zauderer MG, Rusch VW, et al. A phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR T cells: safety and efficacy. Presented at: 2019 AACR Annual Meeting; March 29-April 3, 2019; Atlanta, GA. Abstract CT036. abstractsonline.com/pp8/#!/6812/presentation/9837.