The Changing Paradigm of Cellular Immunotherapy in Cholangiocarcinoma

Dr Eric Tran, PhD, delivered a presentation on the advancements and future directions in cellular immunotherapy for cholangiocarcinoma (CCA). Drawing on his extensive research and training in immunotherapy, Dr Tran discussed the potential of tumor-infiltrating lymphocyte (TIL) therapies, gene-engineered T cells, and novel approaches to harness circulating tumor-reactive T cells.

TIL therapy is an adoptive cell therapy that involves isolating T cells from a patient’s tumor, expanding them in vitro, and infusing them back into the patient. These T cells recognize cancer cells but often lose the battle due to functional suppression or insufficient numbers. By amplifying these T cells outside the body and reintroducing them, researchers aim to enhance their ability to mediate tumor regression. TIL therapy has been shown to be effective in metastatic melanoma, with response rates of 50% and durable responses in 20% to 25% of patients. Some patients have remained cancer-free for over 30 years. Due to these findings researchers have begun to adapt TIL therapy for CCA.

Dr Tran shared the story of a female patient with CCA and metastatic disease in the liver and lung treated at the National Cancer Institute with TIL therapy. After receiving 42 billion TILs and high-dose interleukin-2, her metastatic lung and liver tumors had shown reductions in size. Although her disease stabilized for a year, some lung tumors eventually progressed, prompting researchers to delve deeper into understanding why TIL therapy worked initially and how it could be improved.

Building on this, researchers have advanced TIL therapy by selecting neoantigen-reactive T cells and combining them with immune checkpoint inhibitors like anti–PD-1. Recent clinical trials in metastatic gastrointestinal cancers, including CCA, have demonstrated that this combination improves response rates from 7% to ~24%. One such trial included a patient with CCA who experienced a partial response lasting 17 months, showcasing the potential of this approach.

Gene-engineered T cells involve modifying a patient’s T cells to target specific tumor antigens. Two main types of gene-engineered T cells are T-cell receptor (TCR) gene therapy and CAR T cells. With TCR gene therapy, T cells are modified to express receptors that recognize tumor-specific mutations, such as KRAS or p53. This approach has shown potential in pancreatic cancer, with 1 patient experiencing a 72% tumor reduction. However, it is limited by the need for specific HLA molecules and tumor targets, restricting its applicability. With CAR T cells, T cells are designed to recognize proteins on the tumor surface. Although effective in some cancers, CAR T-cell therapy faces challenges in CCA due to toxicity risks, as many targets are also present on normal tissues. Emphasis was placed on the need to expand the library of TCRs to make gene-engineered T cell therapy accessible to a larger proportion of CCA patients.

The potential of using circulating tumor-reactive T cells from the blood as a less invasive alternative to surgery was explored. Circulating T cells are less exhausted than tumor-derived T cells and can potentially recognize tumors across multiple sites, addressing tumor heterogeneity. However, these cells are rare, often comprising less than 0.1% of all T cells in the blood. Identifying and enriching these tumor-reactive cells is a significant challenge. Dr Tran’s team is actively developing strategies to isolate these cells using biomarkers like PD-1, CD39, CD1, and CD3, and expanding them to therapeutic levels. Early results are promising, with enriched populations of tumor-reactive T cells showing strong potential for therapeutic use.

The presentation concluded by acknowledging the challenges and opportunities in cellular immunotherapy for CCA. Although TIL therapy and gene-engineered T cells have shown promise, their limitations underscore the need for continued innovation. Circulating tumor-reactive T cells represent an exciting frontier, offering a minimally invasive and potentially more effective approach to adoptive cell therapy.

Source: Tran E. The evolving landscape of cellular immunotherapy in cholangiocarcinoma. Presented at: 2026 Annual Cholangiocarcinoma Foundation Conference. May 1-3, 2026; Salt Lake City, UT.