The advent of chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of certain blood cancers that otherwise have limited treatment options. For solid tumors, such as those found in pancreatic, colorectal, and lung cancers, using CAR T cells is more difficult, so they need to be optimized to work differently than in blood cancers. A novel CAR T cell approach that uses logic-gating, now being tested in a solid tumor trial at NYU Langone Health’s Perlmutter Cancer Center, could provide therapeutic benefit for people with such tumors. The first patient dosed globally in the phase 1/2 EVEREST-1 trial was enrolled at Perlmutter Cancer Center, where Salman R. Punekar, MD, leads the study.

The agent, an autologous logic-gated Tmod CAR T-cell product called A2B530, aims to solve a major obstacle in treating solid tumors: how to target the tumor without harming healthy tissue.

A2B530 targets carcinoembryonic antigen (CEA), a common tumor marker in pancreatic, colon, and lung cancers. CEA, however, is also present in normal tissues. Previous studies using CEA-targeting CAR T cells resulted in toxicity for patients because the drug could not distinguish whether a CEA-expressing cell was cancerous or normal. A2B530 is engineered with an inhibitory receptor, or blocker, that can distinguish between healthy and cancerous cells, so that the CAR T cell only activates when it encounters a tumor cell expressing CEA. This is referred to as a logic gate.

“A2B530 is a potentially groundbreaking advance in immunotherapy that could have a major impact for patients with advanced solid tumors without causing the toxicity that we expected to see with the previous generation of CAR T cells,” said Dr. Punekar, an assistant professor in the Department of Medicine at NYU Grossman School of Medicine. “Patients with advanced, metastatic colon, pancreatic, or lung cancer in general don’t have many treatment options. This trial represents an option that could potentially increase their life expectancy.”