First Positive Showing for Mesothelin-Directed CAR T-Cell Therapy in Solid Tumors

June 2019, Vol 10, No 3

Atlanta, GA—Chimeric antigen receptor (CAR) T-cell therapy has had dramatic results in hematologic malignancies, but so far, getting CAR T-cells to work in solid tumors has proved elusive. That may be about to change if promising results from a phase 1 clinical trial are confirmed by further studies. The results of this pivotal study were presented at the 2019 American Association for Cancer Research (AACR) annual meeting.

The phase 1 clinical trial used mesothelin-directed CAR T-cells delivered intrapleurally to the tumor site in patients with mesothelin-associated solid tumors—mostly malignant mesothelioma. The mesothelin-directed CAR T-cell therapy was given in combination with the PD-1 inhibitor pembro­lizumab (Keytruda) as a strategy to prevent T-cell exhaustion and maintain response to treatment.

Early study results in patients who received treatment with the CAR T-cell therapy and at least 3 doses of pembrolizumab showed that this approach was safe and very active after 3 months of follow-up.

The overall response rate was 72% in a subgroup of 11 patients with mesothelioma. This compares favorably with an estimated range of 5% to 29% in patients whose disease progressed while receiving standard platinum-containing chemotherapy, commented lead investigator Prasad S. Adusumilli, MD, FACS, FCCP, Head of Solid Tumors Cell Therapy, Cellular Therapeutics Center, and Deputy Chief, Thoracic Surgery, Memorial Sloan Kettering Cancer Center, New York City.

“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. Treatment with CAR T-cells results in dramatic successes in blood cancers; however, results have been disappointing to date for solid tumors,” Dr Adusumilli said.

“This study strongly supports pursuing 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.

The mesothelin-targeted CAR T-cells attack the cell-surface protein mesothelin, which is expressed in most patients who have mesothelioma. The CAR T-cell therapy incorporates a safety “suicide” switch that can be activated to destroy all CAR T-cells in a patient’s body in the case of unexpected severe toxicity. Regional delivery techniques deposit the CAR T-cells directly to the tumor site.

Study Details

The phase 1 clinical trial enrolled 21 patients with biopsy-proven malignant pleural disease expressing mesothelin; of these, 19 patients had malignant pleural mesothelioma, 1 patient had metastatic lung cancer, and 1 had metastatic breast cancer. Overall, 40% of the patients received a median of 3 regimens, and at least 1 of them was platinum-based. All patients had disease progression while receiving chemotherapy.

The study included 6 dose cohorts. A subset of these patients received the PD-1 inhibitor pembrolizumab as a strategy to maintain response to the mesothelin-directed CAR T-cell therapy.

The mesothelin-directed CAR T-cell therapy was generally well-tolerated, with only grade 1 and 2 adverse events and no evidence of immunogenicity. The CAR T-cells persisted in the peripheral blood for 13 of the 21 patients during the 38-week evaluation period, and persistence was associated with tumor regression on imaging studies.

With a minimum of 3 months of follow-up, the best overall response rate for a subset of 11 patients with malignant pleural mesothelioma who also received pembrolizumab plus lymphodepleting chemotherapy was 72%, including 2 durable complete metabolic responses (ie, no sign of disease on PET scan) and 6 partial responses.

PD-L1 expression level did not correlate with response to treatment. Of the 8 responses, 4 were reported in patients with PD-L1–negative disease.

“The novelty of our study is that the CAR T-cells target the cancer cell-­surface protein, mesothelin, which is expressed on the majority of cancer cells, and they are delivered directly to the tumor site using regional de­livery techniques,” Dr Adusumilli said. “If this approach is successful, 2 million patients with mesothelin-­expressing solid tumors per year in the United States will be eligible for this treatment.”

Durable Responses

“This is one of the most exciting immunotherapy trials in solid tumors. It moves the technology forward,” said Nilofer S. Azad, MD, Co-chair, AACR Clinical Trials Committee and Associate Professor of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, at a press conference at AACR.

Dr Azad cautioned that it was still early days. “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,” she added.

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