Dr Spencer on the Rationale of Evaluating a Novel CAR T-Cell Product in Pancreatic Cancer

“We've seen CAR T[-cell] constructs directed against mesothelin in the past, but they were really limited by on-target, off-tumor toxicity. A2B694 is a novel CAR T[-cell] product that has both an activating and an inhibitory receptor. The activating receptor recognizes mesothelin, both in tumor cells and normal cells, and the inhibitory receptor recognizes HLA-A*02.”

Kristen Spencer, DO, associate professor, Department of Medicine at NYU Grossman School of Medicine; director, Phase 1 Developmental Therapeutics Program, NYU Langone Perlmutter Cancer Center, details the rationale for the phase 1/2 EVEREST-2 trial (NCT06051695) evaluating the CAR T-cell therapy A2B694 in patients with pancreatic cancer or other mesothelin-expressing solid tumors.

The open-label, nonrandomized EVEREST-2 trial is investigating the safety and efficacy of the novel CAR T-cell product, A2B694, for the treatment of patients with mesothelin-expressed tumors, including pancreatic cancer, colon cancer, and other solid tumors, Spencer begins. Previously, there were CAR T constructs that have been directed against mesothelin; however, these constructs were limited by on-target, off-tumor toxicity, she explains. Patients eligible for the trial include those with recurrent, unresectable, locally advanced, or metastatic cancers with mesothelin expression. Enrollment into the EVEREST-2 trial was based on the prescreening BASECAMP-1 study (NCT04981119), which identified patients with tumor-associated HLA-A*02 via next-generation sequencing.

With A2B694, Spencer notes that it has an activating and inhibitor receptor. Specifically, the activating receptor identifies mesothelin in normal and tumor cells, and the inhibitor receptor identifies HLA-A*02, she continues. Because of this factor, she emphasizes that patient selection in this trial is important, especially in determining patients’ germline are heterozygous for HLA-A*02. Afterward, it is key to confirm that patients have a loss of heterozygosity for that allele in the tumor, she says. When this occurs, it protects the normal cells as they engage the inhibitor receptor, which helps destroy tumor cells because they aren’t able to recognize what the inhibitor receptor does, Spencer concludes.