乌鸦传媒

ATLANTA -- Chimeric antigen receptor (CAR) T-cell therapy produced encouraging early signals of activity in solid tumors, according to two preliminary clinical studies reported here.

In one study, CAR T cells targeting the tumor-associated peptide mesothelin led to (MPM), including eight of 11 (73%) patients who received preconditioning therapy, the CAR T cells, and at least three doses of an immune checkpoint inhibitor. Objective responses persisting beyond a year were observed in that subgroup. In the second study, achieved objective responses or stable disease when treated with CAR T cells targeting HER2.

Though numerically modest, the two studies reported at the suggested that appropriately constructed and targeted CAR T-cells have therapeutic potential in solid tumors, following dramatic results in certain types of hematologic malignancies.

"These data are potentially the most compelling CAR T data that we have seen in solid tumors at this point," Nilofer Azad, MD, of Johns Hopkins, said of the MPM study during a press briefing that included the two presentations.

Moving forward, the mesothelin-targeted CARs will be used in concert with anti-PD-1 agents, said Prasad Adusumilli, MD, of Memorial Sloan Kettering Cancer Center in New York City.

"This study strongly supports pursuing CAR T-cell therapy combined with anti-PD-1 strategies in solid tumors," said Adusumilli, lead author on the mesothelioma study. "Our strategy is to make 'cold' tumors 'hot' by injecting CAR T cells first and then activating their function by keeping them 'warm' with an anti-PD-1 agent."

Investigators hope to begin a follow-up trial before the end of the second quarter, giving every patient cyclophosphamide preconditioning, the mesothelin-directed CAR T cells, and an anti-PD-1 agent, he added.

Targeting Mesothelin

MPM arises either as primary mesothelioma or as metastatic disease, most often from lung or breast cancer. The disease has a poor prognosis, and the FDA has not approved a new treatment for malignant pleural mesothelioma since 2003, Adusumilli noted. The disease responds poorly to immune checkpoint inhibition with PD-1/PD-L1 inhibitors.

Mesothelin is a cell-surface antigen that is highly expressed in MPM and a variety of other tumor types and is associated with an aggressive clinical course and poor survival.

Adusumilli and colleagues developed fully human mesothelin-targeting CARs, including a safety switch that can be activated to turn off the CAR T cells in the event of unexpected toxicity. Preclinical studies provided evidence of safety and antitumor activity, but in the presence of a large tumor burden, the CAR T cells became functionally exhausted. Administration of an anti-PD-1 agent rescued T-cell function.

The preclinical safety and efficacy led to the phase I trial reported by Adusumilli, involving 19 patients with mesothelioma and one each with metastatic lung cancer and metastatic breast cancer. The first three patients received only a single intrapleural infusion of the mesothelin-targeted CAR T cells, and the rest had preconditioning with cyclophosphamide, followed by the CAR T-cell infusion.

The results showed no evidence of immunogenicity, as the CAR T-cells persisted in peripheral blood for as long as 48 weeks. Persistence was associated with >50% reduction in mesothelin-related peptide and tumor reduction. The safety analysis showed a single case of grade 3 cyclophosphamide-associated neutropenia. The CAR T-cell therapy was not associated with greater than grade 2 toxicity.

"Most importantly, the neurotoxicity, the severe cytokine release syndrome, and on-target/off-tumor toxicity seen in other trials of CAR T cells, we did not see in our trial," said Adusumilli.

The therapy produced frequent and durable responses, particularly in the patients who received the regimen that will be used in the upcoming trial, he added.

Because of its rarity, mesothelioma is not necessarily a malignancy that has attracted a lot of attention with respect to CAR T-cell development, said Gianpietro Dotti, MD, of the UNC Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina.

"But it does offer the opportunity to infuse the CAR-T cells directly into the pleural cavity where the tumor is located, and then there is this possible association with checkpoint inhibitors," said Dotti, who was not involved in the trial. "When the tumor size is reduced by the CAR-T cell treatment, then there is the possibility to remove it completely with surgery."

"Even if mesothelioma and CAR-T cell delivery into the pleural cavity are a peculiar clinical situation, these results are showing you might be able to achieve some responses in these patients, and it shows we may be starting to have some clinical responses in solid tumors," he added.

HER2-Positive Sarcomas

Development of HER2-targeted CARs followed the observation that the protein is expressed in a variety of sarcomas, including osteosarcoma, and is associated with decreased survival, said Shoba A. Navai, MD, of Baylor College of Medicine in Houston. The 10 patients enrolled in the phase I clinical trial comprised five with osteosarcoma, three with rhabdomyosarcoma, and one each with synovial sarcoma and Ewing sarcoma.The patients had an age range of 4 to 55 and included five female and five males.

After lymphodepleting chemotherapy, each patient received a single infusion of activated CAR T-cells. Evaluation of activity occurred after 6 weeks.

No dose-limiting toxicity occurred, no patient required a transfusion, and no patient developed opportunistic infections, said Navai. Additionally, no persistent pulmonary or cardiac toxicity occurred, no patient developed neurotoxicity, and CRS grade >2 did not occur in any patient. The most common grade 3/4 toxicities were lymphopenia in 10 patients and neutropenia in eight.

One patient with osteosarcoma had a complete response, and two others had stable disease. Two of the three patients with rhabdomyosarcoma had complete responses, and the third had stable disease. The patient with Ewing sarcoma also had stable disease.

During a discussion that followed her presentation, Navai said no decisions had been reached about extending evaluation of the therapy to other HER2-positive cancers. She also said it's too early to conclude that lack of response was related to the therapy or to larger tumor burden.

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