Dr Hecht on the Investigation of A2B530 in Germline HLA-A*02 Heterozygous Solid Tumors

J. Randolph (Randy) Hecht, MD, professor of clinical medicine, the David Geffen School of Medicine, University of California, Los Angeles (UCLA), director, the UCLA Gastrointestinal Oncology Program, discusses the investigation of A2B530 in germline HLA-A*02 heterozygous solid tumors.

A2B530 is a novel CAR T-cell therapy that utilizes the novel Tmod platform, which could allow the therapy to overcome the on-target, off-tumor toxicity that has been an issue associated with CAR T-cell therapy in the treatment of patients with solid tumors.

The BASECAMP-1 trial (NCT04981119) is currently enrolling patients with unresectable locally advanced or metastatic solid tumors, including non–small cell lung cancer, colorectal cancer, mesothelioma, pancreatic cancer, and ovarian cancer. Patients must also have tumors that express CEA, be germline HLA-A*02 heterozygous by HLA typing, and have confirmed somatic loss of heterozygosity by next generation sequencing.

Eligible patients for BASECAMP-1 will undergo apheresis to collect T cells, and upon disease progression, they will be permitted to enroll in the phase 1/2 EVEREST-1 trial (NCT05736731) to receive treatment with A2B530.

The early loss of HLA in tumors can be utilized to distinguish between tumor cells and normal cells, Hecht begins. The goal of A2B530 is to leverage the loss of HLA to create an effective treatment for patients, Hecht expands. A2B530 targets the HLA blocker antigen, and initial studies will utilize HLA-A*02, which was found to be the most common HLA blocker antigen found in North America, Hecht explains.

Although normal cells may express CEA, which is the desired target of A2B530, the normal cells also retain HLA-A*02. Therefore, the blocker antigen will prevent the CAR T-cell therapy from affecting normal tissue, which was demonstrated in preclinical studies, Hecht continues.

In preclinical models, A2B530 has been effective in killing various tumors cells without affecting cells that do not have loss of heterozygosity of HLA. Although the investigation of this novel CAR T-cell therapy is using HLA-A*02 and CEA, other HLA blocker antigens and targets could be explored in the future, Hecht concludes.