Dr Morelli on the Ongoing Investigation of A2B530 in Advanced or Metastatic Solid Tumors

Maria Pia Morelli, MD, PhD, assistant professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the ongoing investigation of A2B530, a Tmod™ CAR T-cell therapy, in advanced or metastatic solid tumors and highlights forward-facing research with the agent.

The novel CAR T-cell therapy is tailored for the purpose of targeting tumors that exhibit carcinoembryonic antigen (CEA) while lacking the HLA-A*02 antigen. A2B530 is being investigated in the phase 1/2 EVEREST-1 trial (NCT05736731), which aims to evaluate the agent in patients with recurring, unresectable, locally advanced, or metastatic solid tumors that express CEA and lack HLA-A*02.

Implementing a blocker mechanism holds the potential to broaden the spectrum of targetable elements in oncology, Morelli begins. CEA is prevalent in colorectal and pancreatic cancers, both of which are being studied in phase 1/2 EVEREST-1 clinical trial, as well as lung and ovarian cancers, she states. Presently, investigators are exploring mesothelin, which has garnered considerable interest over the years as a CAR T-cell therapy target, she notes. However, its use has been hindered by adverse effects (AEs), which primarily arise because of its presence in healthy tissues, Morelli explains. With the incorporation of the blocker, investigators can now consider leveraging mesothelin as a therapeutic target, particularly in the management of diseases such as ovarian cancer, lung cancer, pancreatic cancer, and mesothelioma, she expands. This expansion prompted the launch of the EVEREST-1 trial, which is exploring CEA-directed therapy, as well as the inception of the phase 1/2 EVEREST-2 trial (NCT06051695), which is investigating mesothelin as a target in patients with solid tumors, Morelli emphasizes.

Overall, using a blocker expands the availability of more targets and substantially widens the solid tumor therapeutic window, Morelli continues. This widened scope enables the administration of higher doses of CAR T cells to enhance their activity without the concern of severe AEs that could be life threatening in certain scenarios, she says. Moreover, the consideration of the antigen HLA-A*02 is crucial, particularly given its prevalence in populations of patients with solid tumors. Consequently, investigators’ efforts are directed towardadvancing therapeutic approaches with this target, she concludes.