Advancing CAR T Cell Therapy for Cholangiocarcinoma

Dr Mitchell Ho presented on the development of CAR T-cell therapy in cholangiocarcinoma (CCA). His research explores cancer-promoting proteins and advances the design of specific, potent immunotherapies to overcome the challenges posed by solid tumors like CCA.

Despite its success in treating hematologic cancers, CAR T-cell therapy faces barriers in solid tumors including a dense extracellular matrix, an immunosuppressive tumor microenvironment, and physiological barriers that impede T-cell penetration. Therefore, the application of CAR-T cell therapy in solid tumors, including CCA, presents unique challenges that require advanced protein and CAR T-cell engineering, such as optimizing antibody structure, modifying hinge and transmembrane domains, and enhancing T-cell potency to achieve effective antitumor activity.

Successful treatment depends on identifying the correct tumor-specific antigen. CAR T cells must aim for cancer cells but avoid harming healthy cells, making the selection of an optimal target critical. This research focuses on glypicans and mesothelin, proteins that are expressed on the surface of CCA cells, making them potential candidates for CAR-T cell therapy.

Dr Ho’s research team has studied glypican-1, glypican-2, and glypican-3, for nearly 2 decades. These proteins are involved in cancer-promoting pathways, such as Wnt and YAP signaling, and are highly expressed in various cancers, including CCA. Additionally, using a humanized antibody called YP7, CAR T cells were developed that demonstrated potent antitumor activity in preclinical models of hepatocellular carcinoma. These results prompted the team to expand its focus to CCA, where glypican-1 is expressed.

Mesothelin is a protein expressed in CCA whose interaction with the protein CA-125 facilitates tumor spread and makes it a target. To enhance antigen-specific recognition and cytotoxic activity of CAR T cells against CCA, advanced protein engineering techniques were employed to optimize CAR T design, including heavy/light chain reorientation, modifying hinge regions, and antibody humanization to reduce immunogenicity and improve efficacy. Through these techniques, an optimized mesothelin-targeted CAR T-cell construct was developed that showed notable improvement in CCA models. In preclinical studies it achieved complete tumor regression.

In clinical evaluation, mesothelin-targeted CAR T cells are being evaluated in patients with mesothelioma. The team plans to expand these trials to include CCA within the next year. Furthermore, Dr Ho’s team has partnered with researchers at Mahidol University in Thailand to develop CAR T therapies tailored for the high incidence of CCA caused by liver fluke infections.

Although CAR T-cell therapy faces obstacles, they are not insurmountable. Its success will depend on our ability to engineer potent immune cells and identify the right targets. As the research landscape of CAR T-cell therapy continues to develop, it offers an outlook where personalized, targeted immunotherapy has the potential to alter CCA treatment.

Source: Ho M. Development of CAR T cell therapies for cholangiocarcinoma. Presented at: 2026 Annual Cholangiocarcinoma Foundation Conference. May 1-3, 2026; Salt Lake City, UT.