Dr Creelan on the Investigation of A2B530 in Advanced or Metastatic NSCLC

Benjamin Creelan, MD, thoracic oncologist, Moffit Cancer Center, discusses the investigation of A2B530 in patients with advanced or metastatic non–small cell lung cancer (NSCLC).

A2B530 is a Tmod™ CAR T-cell therapy specifically designed to target tumors expressing carcinoembryonic antigen (CEA) that lack the HLA-A*02 antigen. A2B530 is currently under investigation in the phase 1/2 EVEREST-1 clinical trial (NCT05736731). This trial is structured to assess patients with CEA-expressing recurring, unresectable, locally advanced, or metastatic NSCLC, colorectal cancer, and pancreatic cancer.

One method for mitigating off-target toxicity associated with CAR T-cell therapy involves implementing either an "on/on" requirement or an "on/off" requirement within the T cell, a concept known as logic gating, Creelan begins. This approach employs a second signal in the T cell, prompting it to deactivate upon encountering a normal marker or to activate only in the presence of 2 abnormal markers. This strategy enhances the T cell's specificity, directing its activity against the tumor while minimizing damage to normal tissue, Creelan explains. Presently, there is a reexamination of CAR T-cell therapy–directed biomarkers that previouslyexhibited excessive toxicity, with a renewed focus on introducing new receptors and switches to enhance the specificity of those biomarker-directed therapies, he states

An example of this approach is the use of a Tmod therapy, such as A2B530, which incorporates an off switch triggered by the presence of an HLA marker, such as HLA-A*02, he expands.Typically, normal cells possess both HLA genes, whereas in tumor cells, 1 of these genes is often deleted, Creelan says, adding that a CAR T-cell that activates only in the absence of HLA and in the presence of a common tumor antigen shows promise in this setting.

The Tmod approach targets CEA, a marker that once produced promising responses but resulted in excessive colitis. By incorporating a logical switch into CEA-directed therapies, the aim is to eliminate colitis and other associated toxicities while maintaining efficacy against the tumor, he continues. This strategy isn't limited to a single marker; other HLA types and markersare under investigation, Creelan emphasizes. By employing a CAR T-cell therapy with an off switch, the hope is to maintain efficacy while minimizing adverse effects. While the effectiveness of this approach in patients is yet to be fully observed, preclinical data presentencouraging evidence, he concludes.