Trispecifics: A New Strategy to Prevent Antigen Escape

As bispecific T-cell engagers expand into community practice, trispecific antibodies are emerging as a potential next step in T-cell–based immunotherapy. In an interview, Krish Patel, MD, executive director of hematologic cancer research at Sarah Cannon Research Institute, discusses the rationale behind trispecific T-cell engagers and how these therapies could address a key mechanism of resistance to bispecifics: tumor antigen loss.

Bispecific T-cell engagers typically target 1 antigen on a tumor cell while simultaneously engaging an antigen on a T cell, bringing the immune cell into contact with the cancer. However, cancer cells can escape treatment by losing the tumor antigen targeted by the bispecific, either under treatment pressure or because the antigen was not present initially. Patel notes that antigen loss has been observed in lymphoma, multiple myeloma, and leukemia.

Trispecifics could potentially address this challenge by targeting 2 different tumor antigens instead of 1. By maintaining activity against cancer cells that retain either antigen, this approach may make it more difficult for tumors to evade treatment through antigen loss. Patel also discusses a second strategy being explored with trispecifics: engaging 2 different immune-cell targets while maintaining a single tumor antigen target. This approach could potentially recruit additional immune-cell functions or enhance T-cell–mediated tumor killing.

With advances in antibody engineering enabling increasingly complex targeting strategies, trispecifics represent an emerging approach to overcoming resistance and expanding the capabilities of T-cell–engaging therapies.