番茄社区

CHICAGO -- Two different chimeric antigen receptor (CAR) T-cell therapies showed activity in solid tumors, according to preliminary trial data reported here.

Mesothelin-targeted CAR T cells, combined with a PD-1 inhibitor, led to complete responses in 10 of 16 patients with heavily pretreated pleural mesothelioma. Three patients achieved complete responses with the combination, said , of Memorial Sloan Kettering Cancer Center in New York City.

And in a separate study, CAR T cells targeting claudin 18.2 (a structural molecule found in many types of epithelial cells) led to objective responses in four of 12 patients with advanced gastric cancer and stable disease in five others.

Additional studies of both therapies are either ongoing or planned, as reported at the annual meeting.

Adusumilli said the results of combination therapy "strongly support pursuing CAR T-cell therapy combined with PD-1 blocking strategies in solid tumors. In other words, transforming 'cold' tumors into 'hot' ones and keeping them warm."

To date, the major successes of CAR T-cell therapy have occurred in hematologic malignancies. The two currently approved agents have indication in leukemia and lymphoma. Translating that success into solid tumors poses a number of challenges, not the least of which is identifying suitable targets for the therapy. Both of the approved CAR T-cell therapies target CD19, an antigen associated with B cell development.

Targeting Mesothelin

Mesothelin is a cell-surface antigen expressed by a majority of solid tumors and is a marker of tumor aggressiveness. Collectively, mesothelin-expressing tumors have an annual incidence of 372,000, said Adusumilli. Pleural cancers, both primary and metastatic, are among those that express mesothelin. Malignant pleural mesothelioma represents a major unmet need in oncology, as no treatment has been approved since 2003 and current therapies barely make a dent in survival.

Adusumilli and colleagues developed a fully human mesothelin CAR. In , they demonstrated that intrapleural administration of the CAR led to rapid T-cell activation and CAR T-cell expansion, leading to enhanced antitumor activity and persistence of functional T cells.

Promising laboratory and early clinical results led to a phase I clinical trial involving patients with mesothelioma and pleural metastases from lung or breast cancer. Successful CAR T-cell transduction occurred in all 27 patients enrolled to date.

The patients had previously treated tumors, and more than a third had received three or more prior lines of therapy. After the first three patients had been treated, all subsequent patients received cyclophosphamide preconditioning. Additionally, 22 of the patients also received a PD-1 inhibitor.

The rationale for adding the latter came from showing that anti-PD-1 therapy rescued CAR T cells from tumor-induced exhaustion. In addition, guidelines specify checkpoint blockade as a second-line treatment option for mesothelioma.

"Intrapleural CAR T cells and systemic anti-PD1 antibody administration was well tolerated," said Adusumilli. "We observed no evidence of CAR T-cell-related adverse events of grade 2 or greater, including no neurotoxicity, no cytokine release syndrome (CRS), and no on-target or off-target toxicity."

The most common adverse event was flu-like symptoms in six patients. One patient developed grade 3 febrile neutropenia associated with the cyclophosphamide.

No patient had an objective response before the PD-1 inhibitor was added to the treatment protocol. Among 16 patients who received cyclophosphamide, the CAR T-cell therapy, and the PD-1 inhibitor, the objective response rate was 63%. Two other patients had stable disease.

With a median follow-up of 8.4 months, 23 evaluable patients had a 6-month overall survival (OS) of 90.3% and 12-month OS of 74.1%. The 16-patient subgroup, with median follow-up of 11.8 months, had 6-month OS of 100% and 1-year OS of 80.2%.

Gastric, Pancreatic Cancers

Similar to mesothelin, claudin 18.2 is expressed by a diverse variety of epithelial tumors. With respect to gastric cancer, claudin 18.2 expression is limited to differentiated epithelial cells of the gastric mucosa, said , of Shanghai Hospital and the Second Military Medical University in China. Studies involving preclinical models of gastric cancer showed that CAR T cells targeting claudin 18.2 had potent antitumor activity.

Li reported initial results from a phase I trial of the claudin 18.2 CAR T-cell therapy in patients with advanced gastric or pancreatic cancer. All of the patients had progressive disease with prior therapy or had declined other forms of treatment, including surgery. Eligibility criteria included an expected survival of at least 12 weeks.

To date, Li and colleagues have treated 12 patients, seven with gastric cancer and five with pancreatic cancer. She said the claudin 18.2-transduced T cells were successfully generated for all 12 patients, following preconditioning with chemotherapy.

All of the patients developed one or more grade ≥3 treatment-related adverse events, including hematologic toxicity in all 12. Li noted that no patient developed CRS worse than grade 2 and no patient had symptoms of neurotoxicity. Two patients had grade 2 on-target toxicity (gastric hemorrhage/mucosal injury) related to the CAR T-cell therapy. No patient had treatment-related serious adverse events.

Nine of the 12 patients had some degree of tumor shrinkage. One patient with gastric cancer had a complete response, and two others had partial responses. One patient with pancreatic cancer had a partial response. The disease control rate (response plus stable disease) was 75%.