Development and clinical testing of effective immunotherapies for biliary tract cancers

Biliary Tract Cancer (BTC), including cholangiocarcinoma and gallbladder cancer, are relatively rare cancers (~1,000 cases diagnosed in Canada per year) associated with a dismal prognosis, particularly when diagnosed at stage IV. 

Due to progress in molecular oncology, new therapies are being tested or recently approved in cholangiocarcinoma. This includes a Health Canada approval of the FGF2 (Fibroblast Growth Factor) Receptor antagonists, pemigatinib for patients with a FGF2R mutation, and numerous clinical trials of molecularly targeted agents for about 45% of BTC patients with other actionable mutations, fusions or amplifications (e.g. IDH, NTRK, ERBB2, CDK6 and MSI). Our biobank and prospective registry of patients with resected bile duct cancers, all a high risk of recurrence, constitute an important resource to evaluate in what proportion of patients these novel agents could be tested in the adjuvant setting. The sequencing data linked to real world, extensive clinical data in this cohort will inform the design of future studies. 

Progress has also been made in immunotherapy of bile duct cancer, a crucial new therapeutic avenue since patients with actionable mutations eligible for molecular targeted therapy all face treatment resistance. Combining the Immune checkpoint inhibitors targeting PD-L1 and PD-1, combined with standard chemotherapy, have resulted in significant progression free survival benefits compared to standard chemotherapy alone. Nonetheless, 90% of patients still progress. for BTC patients treated with durvalamab and chemotherapy. A more powerful T cell-based immunotherapy consisting in transfusing patients their own tumor infiltrating T lymphocytes (TIL) expanded ex-vivo from a surgically removed tumor deposit is currently being developed for various solid cancer. Dr. Simon Turcotte has contributed to a first proof of concept that TIL immunotherapy could mediate response in metastatic bile duct cancer. At the Centre hospitalier de l’Université de Montréal, Dr. Turcotte has develop the capacity to manufacture TIL and execute TIL therapy. In collaboration with  collaborators Dr. Rebecca Auer and Carolina Ilkow at the Ottawa Hospital, Dr Turcotte is activating a two-center TIL immunotherapy study for patients with metastatic bile duct cancer and a research program investigating the immune features of bile duct cancers. Sequencing through the MOH project is critical for TIL manufacturing given that the process involves selecting T cells reactive to peptides derived from somatic mutations (neoantigens), as well as for the discovery of novel types of antigens that may be recognized by TIL. Beyond the number and the types of genomic alterations find in these tumors, transcriptomic signatures associated with TIL successful manufacturing and clinical response will be central to correlative research.