Immunotherapy in biliary tract cancers: Current landscape and emerging directions

INTRODUCTION

Biliary tract cancers (BTCs) are a diverse group of epithelial tumors that originate in the biliary tree. This category includes intrahepatic cholangiocarcinoma (iCCA), perihilar cholangiocarcinoma, distal cholangiocarcinoma, and gallbladder carcinoma (GBC).^[1] The incidence of BTCs is increasing globally, particularly in regions such as Southeast Asia and South America.^[2] Most patients are diagnosed at an advanced stage owing to a lack of early symptoms and the absence of effective screening strategies. Surgical resection is the only potentially curative treatment available, but it is an option for only a small number of patients.^[3]

The landmark ABC-02 trial established the combination of cisplatin and gemcitabine as the first-line systemic chemotherapy, leading to a median overall survival (OS) of 11.7 months.^[4] Despite this treatment, the prognosis for patients remains poor, with 5-year survival rates rarely exceeding 10% in cases of advanced disease.^[5] The introduction of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has transformed treatment approaches for several solid tumors, and research is now exploring their use in BTCs.^[6]

TUMOR IMMUNOBIOLOGY IN BTC

BTCs are typically characterized by an immunosuppressive tumor microenvironment (TME) that limits effective immune surveillance. Key features of BTCs include a dense desmoplastic stroma, a lack of effector T cells, and an abundance of regulatory T cells (Tregs) and myeloid-derived suppressor cells, all of which inhibit anti-tumor immunity.^[7,8] In addition, tumor-associated macrophages in BTCs predominantly exhibit an M2-like phenotype, which promotes tumor progression and immune evasion.^[9]

Moreover, programmed death-ligand 1 (PD-L1) expression in BTCs varies significantly, with reported rates ranging from 9% to 72%, depending on the specific assay and tumor subtype.^[10] While BTCs generally have a low tumor mutational burden (TMB), a small proportion may exhibit microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) characteristics, which increase the likelihood of responsiveness to ICIs.^[11,12]

The immune microenvironment of BTCs can differ among subtypes, with iCCA typically showing a higher level of immune cell infiltration compared to extrahepatic cholangiocarcinoma or GBC.^[13] This biological diversity highlights the need for tailored immunotherapy approaches.

ICIS IN BTCS

BIOMARKERS OF RESPONSE

Effective biomarkers are crucial for identifying patients with BTC who are most likely to benefit from immunotherapy. PDL1 expression, although evaluated in several trials, has shown inconsistent correlation with response.^[10,15] TMB is generally low in BTCs, which limits its utility in predicting treatment responses.^[24] MSI-H and dMMR statuses are well-established predictors of response to ICIs; however, their low prevalence reduces their significance on a population level.^[19] Emerging biomarkers for evaluating immune response include tumor-infiltrating lymphocytes (TILs), immune gene expression profiles, and neoantigen load.^[25] In addition, genetic alterations such as Isocitrate dehydrogenase (IDH) 1/2 mutations and fibroblast growth factor receptor 2 (FGFR2) fusions, which are primarily targeted by small-molecule inhibitors, may also impact immune responsiveness by modifying the TME.^[26,27] Furthermore, the gut microbiome, known to affect ICI response in other cancers, is currently being investigated in the context of BTC.^[28]

EMERGING IMMUNOTHERAPEUTIC STRATEGIES

HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR-2 (HER2) POSITIVE BTC

HER2 overexpression is seen in 10–15% of patients in India. The role of HER2-directed therapy in the first-line setting has not been established. Muddu et al. performed a retrospective analysis to evaluate the combination of trastuzumab, ICIs, and chemotherapy in HER2-positive advanced BTC. The median PFS was 6 months, and the estimated OS was 20 months.^[38]

ONGOING CLINICAL TRIALS

Numerous ongoing clinical trials aim to evaluate the combination of immunotherapy in BTC. Newer drugs targeting T-cell immunoglobulin and mucin domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT) are also entering early-phase trials.^[39,40] Ying et al. demonstrated a median PFS of 8.5 months with ivonescimab, a tetrameric bispecific antibody targeting PD-1 and VEGF, when added to gemcitabine and cisplatin. Further trials are necessary to validate safety and efficacy.^[41]

The combination of nivolumab and entinostat, a histone deacetylase inhibitor, with or without ipilimumab, has shown promise in phase I trials for advanced solid tumors and may represent one of the most promising options in the future.^[42]

The ENLIGHTEN study, a phase II trial of envafolimab combined with lenvatinib, gemcitabine, and cisplatin, also showed promising results. Further Phase III trials are necessary to confirm the efficacy of this combination.^[43]

REAL-WORLD DATA AND CHALLENGES

Muddu et al. conducted a multicenter retrospective study across 14 centers in India to evaluate the safety and efficacy of the combination of durvalumab with gemcitabine and cisplatin. The study noted a median PFS of 8.2 months and a median OS of 12 months. Grade 3 or 4 irAEs occurred in 7.4% of the participants.^[44]

Despite these promising trial results, challenges persist in real-world settings. Limited access to immunotherapy due to high costs, logistical constraints, and the availability of biomarker testing hinders implementation in low- and middle-income countries.^[45] Adopting low-dose immunotherapy options could be of significant benefit. Patel et al. evaluated the effectiveness of low-dose ICIs across various tumor types, which included 11 patients with BTC.^[46]

In addition, the rarity and heterogeneity of BTCs pose difficulties in trial enrollment and data generalization. irAEs also require multidisciplinary management, which may not be readily available in all settings.^[47]

FUTURE DIRECTIONS

Future research in BTC immunotherapy should focus on biomarker-driven trial designs, the integration of novel immune modulators, and the exploration of neoadjuvant and adjuvant treatment settings.^[48,49] Personalized cancer vaccines, oncolytic viruses, and microbiome-based therapies have the potential to expand the population eligible for immunotherapy. In addition, advances in organoid modeling and single-cell sequencing may help clarify resistance mechanisms and guide strategies for combination therapies.^[50]

CONCLUSION

Immunotherapy resulted in a paradigm shift in the management of BTCs. While only a subset of patients benefit currently, landmark trials like TOPAZ-1 have established a new standard of care. As our understanding of BTC immunobiology deepens and novel strategies are explored, the therapeutic armamentarium for these aggressive malignancies is set to expand.