A phase I clinical trial showed encouraging results with chimeric antigen receptor (CAR) T-cell therapy targeted to the mesothelin protein in patients with mesothelin-associated malignant pleural solid tumors—primarily, malignant mesothelioma—that had progressed following standard platinum-based chemotherapy. In this study, the CAR T-cell therapy was delivered intrapleurally to the site of the tumor.

The innovative targeted CAR T-cell treatment was safe and showed early promise. Response was evaluated in a group of patients who received at least three doses of anti–programmed cell death protein 1 (PD-1) therapy with pembrolizumab in combination with the mesothelin-directed CAR T cells. Based on the results of the trial, the authors are planning a combination trial of anti–PD-1 plus mesothelin-targeted CAR T cells in patients with mesothelin-associated solid tumors in the second quarter of 2019.

The phase I trial is one of the first studies to demonstrate the potential applicability of CAR T-cell therapy in solid tumors. The data were presented at the 2019 Annual Meeting of the American Association for Cancer Research (AACR).¹

If this approach is successful, 2 million patients with mesothelin-expressing solid tumors per year in the United States will be eligible for the treatment.

— Prasad S. Adusumilli, MD

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“Patients with advanced-stage solid tumors, such as mesothelioma and lung and breast cancers that are metastatic to the chest cavity, have poor outcomes despite treatment,” said lead author Prasad S. Adusumilli, MD, Deputy Chief of Thoracic Surgery at Memorial Sloan Kettering Cancer Center in New York. “Treatment with CAR T cells results in dramatic successes in blood cancers. However, results have been disappointing to date for solid tumors.”

Michel Sadelain, MD, PhD

He continued, “In this phase I clinical trial, intrapleurally administered mesothelin-targeted CAR T cells had no evidence of ‘on-target, off-tumor’ or therapy-related major toxicity, but there was evidence of CAR T-cell antitumor activity.” The senior study author was Michel Sadelain, MD, PhD, of Memorial Sloan Kettering.

“This is one of the most exciting immunotherapy trials in solid tumors. It moves the technology forward,” stated Nilofer Azad, MD, Professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore. Dr. Azad, who moderated a press conference where these data were discussed, was cautiously optimistic because they are still very early data.

How Does It Work?

The mesothelin-targeted CAR T cells are called icasM28z and comprise only human components, a first-in-the world to reduce the chance of immunogenicity. The product includes the inducible caspase-9 safety “suicide” switch, which can be activated to destroy all CAR T cells in a patient’s body in the case of unexpected severe toxicity.

An important aspect of this study is the observation that when CAR T cells work, they expand. It may be that the actual dose used is less important than documenting expansion.

— Nilofer Azad, MD

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The targeted CAR T cells attack the cell-surface protein mesothelin, which is expressed in the majority of cancer cells in mesothelioma. Regional delivery techniques deposit the CAR T cells directly to the tumor site.

“If this approach is successful, 2 million patients with mesothelin-expressing solid tumors per year in the United States will be eligible for the treatment,” Dr. Adusumilli told listeners.

Study Background

Pleural cancers occur in about 150,000 patients each year in the United States. Malignant pleural mesothelioma is a primary tumor, and metastatic pleural cancers are common in patients with breast and lung cancers.

Malignant pleural mesothelioma is an aggressive solid tumor, associated with an expected overall survival and progression-free survival benefit of about 3 to 5 months with current therapies. Responses to checkpoint inhibitor immunotherapy are poor, but anti–PD-1 therapy is included as a second-line therapy for the disease in the National Comprehensive Cancer Network^® Clinical Practice Guidelines in Oncology.

Mesothelin-expressing solid tumors account for 371,977 tumors in the United States. “Mesothelin expression is common in these tumors, and it is associated with aggressiveness,” Dr. Adusumilli noted.

Preliminary studies in clinically-relevant orthotopic mouse models provided a rationale for intrapleural administration of mesothelin-targeted CAR T cells. These studies also found that CAR T cells are functionally exhausted in the presence of a large tumor burden, but administration of an anti–PD-1 agent restores CAR T-cell function.

Thus, pembrolizumab was added to CAR T-cell administration 6 to 8 weeks later. Dr. Adusumilli presented results for 11 patients who received CAR T-cell infusion and at least 3 doses of anti–PD-1 agent with a minimum follow-up of 3 months.

Methodology and Findings

The phase I study is part of the Stand Up to Cancer initiative supporting clinical trials to expand the use of autologous CAR T-cell immunotherapy beyond hematologic cancers to solid tumors, including mesothelioma and osteosarcoma. The study enrolled 21 patients with biopsy-proven malignant pleural disease expressing mesothelin; 19 had malignant pleural mesothelioma, 1 had metastatic lung cancer, and 1 had metastatic breast cancer. All patients had disease progression on a median of three prior regimens.

The study included six dose cohorts with the CAR T-cell product administered directly to the tumor site using regional delivery techniques. Patients were initially treated with a low CAR T-cell dose without lymphodepleting chemotherapy, followed by increasing doses of CAR T cells with lymphodepletion. A subset of these patients received pembrolizumab to maintain a response to the mesothelin-directed CAR T-cell therapy.

The treatment was generally well tolerated, with grade 1 and 2 toxicities. No immunogenicity was found, as measured by CAR T-cell persistence in the peripheral blood. The CAR T cells persisted in the peripheral blood for 13 of 21 patients during the 38-week evaluation period. The presence of persistent CAR T cells was associated with tumor regression on imaging.

With a minimum of 3 months of follow-up, the best overall response for a subset of 11 patients with malignant pleural mesothelioma was 72%, including 2 durable complete metabolic responses (ie, no signal of disease presence on positron-emission tomography) and 6 partial responses. All of these patients had received lymphodepleting chemotherapy prior to CAR T cells and pembrolizumab after CAR T, Dr. Adusumilli noted. Nine of these patients had programmed cell death ligand 1 (PD-L1)-low (≤ 10%) of tumor cells by immunohistochemistry, and 6 of 8 responses were seen in PD-L1–low patients.

The overall response rate of 72% compares favorably with current therapies. “This study strongly supports the continued testing of CAR T-cell therapy combined with anti–PD-1 strategies in solid tumors. This strategy transforms [immunologically] ‘cold’ solid tumors to ‘hot’ tumors and keeps them warm,” Dr. Adusumilli stated.

Additional Comments on the Study

At the press conference, Dr. Azad said there are caveats with this study. “It has taken many years of study by many groups of researchers to optimize CAR T-cell therapy. This early study shows a durable benefit in a sizable proportion of patients. The authors plan to build on this combination, because mesothelin is an important target to address.”

“An important aspect of this study is the observation that when CAR T cells work, they expand. It may be that the actual dose used is less important than documenting expansion,” Dr. Azad continued.

She was also optimistic about the combination of anti–PD-1 with CAR T cells. “This strategy helps maintain the response to CAR T,” she noted.

Marcela Maus, MD

Marcela Maus, MD, of Massachusetts General Hospital, Boston, also expressed enthusiasm about this study. “Using autologous CAR T cells engineered to target mesothelin, administered to the pleural cavity after lymphodepletion, holds great promise. Even though this is a small study, the 72% response rate is exciting. These responses validate that CAR T-cell therapy can work in solid tumors,” Dr. Maus stated.

“Prior to this study, there had been only one case report of a response to CAR T cells in a solid tumor. Other than those limited data, we had no other evidence until now that CAR T can induce responses in solid tumors,” Dr. Maus continued.

“An important piece of this study is that rejuvenating CAR T cells with anti–PD-1 is useful. Perhaps delivering CAR T cells locally to the tumor site along with an anti–PD-1 agent will transform the field [of treating solid tumors with CAR T cells],” she said. ■

DISCLOSURE: Dr. Adusumilli’s financial disclosures included research grants from OSE Immunotherapeutics, ACEA Biosciences, and Atara Biotherapeutics. He has received licensing and royalty fees for CAR products licensed to Atara Biotherapeutics. Dr. Azad reported no conflicts of interest. Dr. Maus has stock and other ownership interests in Agenus; has received honoraria from BD Biosciences and Cell Signaling Technology; is or has been a consultant/advisor for Agenus, TCR2 Therapeutics, WindMIL, Adaptimmune, Arcellx, Bluebird Bio, CRISPR Therapeutics, EMD Serono, Kite Pharma, Novartis, Takeda, Torque, and Cellectis; has received research funding from Agenus, TCR2 Therapeutics, CRISPR Therapeutics and Kite Pharma; is an inventor on patents held by the University of Pennsylvania with and without Novartis and Massachusetts General Hospital/Partners HealthCare, related to CAR T-cell and/or gene therapy; and has received travel/accommodations/expenses from GlaxoSmithKline and BD Biosciences.

REFERENCE

1. Adusumilli PS, Zauderer M, Rusch V, et al: A phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR-T cells. 2019 AACR Annual Meeting. Abstract CT036. Presented March 31, 2019.