Biliary tract cancers (BTCs), comprising intrahepatic, perihilar, and distal cholangiocarcinoma as well as gallbladder adenocarcinoma, continue to be challenging to manage. Conventional chemotherapy regimens for advanced disease are limited in both options and benefits, and more effective perioperative regimens are also needed. Over the last decade, immunotherapy has had a profound impact on the management of many solid tumor types, particularly in using immune checkpoint inhibition to enable a tumor-directed T cell response. Immunotherapy administered on its own has had limited utility in BTCs, in part due to a hostile immune microenvironment and the relative infrequency of biomarker-based tumor-agnostic indications for immunotherapy. However, immunotherapy in conjunction with chemotherapy, molecularly targeted therapies, and/or anti-angiogenic therapies has gained traction, supported by evidence that these agents can impart favorable immunomodulatory effects on the tumor microenvironment. The TOPAZ-1 trial led to the first BTC-specific immunotherapy approval, establishing the combination of durvalumab with gemcitabine and cisplatin as the preferred first-line treatment for advanced or metastatic disease. Recently, the KEYNOTE-966 trial showed positive results for the combination of pembrolizumab with gemcitabine and cisplatin in the same setting, adding further evidence for the addition of immune checkpoint inhibition to the standard chemotherapy backbone. Meanwhile, advances in the molecular profiling of BTCs has contributed to the recent proliferation of molecularly targeted therapeutics for the subset of BTCs harboring alterations in IDH1, FGFR2, MAP kinase signaling, HER2, and beyond, and there has been great interest in investigating combinations of these agents with immunotherapy. Emerging immunotherapy strategies beyond immune checkpoint inhibition are also being studied in BTCs, and these include immunostimulatory receptor agonists, Wnt signaling modulators, adoptive cell therapy, and cancer vaccines. A large number of trials are underway to explore promising new combinations and immune-targeted strategies, offering opportunities to expand the role of immunotherapy in BTC management in the near future.

Opinion statement: Biliary tract cancers are molecularly and anatomically diverse cancers which include intrahepatic cholangiocarcinoma, extrahepatic (perihilar and distal) cholangiocarcinoma, and gallbladder cancer. While recognized as distinct entities, the rarer incidence of these cancers combined with diagnostic challenges in classifying anatomic origin has resulted in clinical trials and guideline recommended strategies being generalized patients with all types of biliary tract cancer. In this review, we delve into the unique aspects, subtype-specific clinical trial outcomes, and multidisciplinary management of patients with extrahepatic cholangiocarcinoma. When resectable, definitive surgery followed by adjuvant chemotherapy (sometimes with selective radiation/chemoradiation) is current standard of care. Due to high recurrence rates, there is growing interest in the use of upfront/neoadjuvant therapy to improve surgical outcomes and to downstage patients who may not initially be resectable. Select patients with perihilar cholangiocarcinoma are being successfully treated with novel approaches such as liver transplant. In the advanced disease setting, combination gemcitabine and cisplatin remains the standard base for systemic therapy and was recently improved upon with the addition of immune checkpoint blockade to the chemotherapy doublet in the recently reported TOPAZ-1 and KEYNOTE-966 trials. Second-line all-comer treatments for these patients remain limited in both options and efficacy, so clinical trial participation should be strongly considered. With increased use of molecular testing, detection of actionable mutations and opportunities to receive indicated targeted therapies are on the rise and are the most significant driver of improved survival for patients with advanced stage disease. Though these targeted therapies are currently reserved for the second or later line, future trials are looking at moving these to earlier treatment settings and use in combination with chemotherapy and immunotherapy. In addition to cross-disciplinary management with surgical, medical, and radiation oncology, patient-centered care should also include collaboration with advanced endoscopists, palliative care specialists, and nutritionists to improve global patient outcomes.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and, with only 15–20% of HCC patients being suitable for potentially curative treatments, the vast majority of patients with HCC ultimately require systemic therapy. For decades, the choice of effective systemic therapy for HCC remained sparse. In recent years, after the combination of atezolizumab and bevacizumab demonstrated superior overall survival over the first-line standard, sorafenib, there has been a major therapeutic paradigm shift to immunotherapy-based regimens for HCC. While representing a great leap forward for the treatment of this cancer, the reality is that less than one-third of patients achieve an objective response to immune checkpoint inhibitor-based therapy, so there remains a significant clinical need for further therapeutic optimization. In this review, we provide an overview of the current landscape of immunotherapy for unresectable HCC and delve into the tumor intrinsic and extrinsic mechanisms of resistance to established immunotherapies with a focus on novel therapeutic targets with strong translational potential. Following this, we spotlight emerging immunotherapy approaches and notable clinical trials aiming to optimize immunotherapy efficacy in HCC that include novel immune checkpoint inhibitors, tumor microenvironment modulators, targeted delivery systems, and locoregional interventions.

Recent advancements in understanding the biology of glioblastomas (GBM) and increasing adoption of genomic sequencing in oncology practice have led to the discovery of several targetable mutations in these cancers. Among them, the BRAF V600E mutation can be found in approximately 3% of GBM. Despite the aggressive nature of GBM, metastatic disease is rarely observed. While there are growing data utilizing BRAF-targeting strategies in patients with GBM, data examining their efficacy in cases of metastatic GBM are lacking. We present the case of a 46-year-old female with GBM, isocitrate dehydrogenase (IDH)-wildtype and O⁶-methylguanine-DNA methyltransferase promoter (MGMT) unmethylated, BRAF V600E-mutant, and MYC amplified with extra-central nervous system spread to the spine and lung. Four months after completion of treatment with standard chemoradiation and temozolomide, the patient developed severe back pain, leading to the eventual discovery of her metastatic disease. Based on the presence of the BRAF V600E mutation, the patient was treated with and achieved an intracranial and systemic response to combination BRAF-MEK targeted inhibition for 9 months before evidence of progression.

Background and Aims: Although chemotherapy and anti-PD-L1 antibodies are the standard of care for cholangiocarcinoma (CCA), resistance is common and limits durable benefits for patients. This hurdle underscores the urgent need to innovate combination approaches that promote durable immunity in patients. MEK inhibitors (MEKi) have shown potential to enhance immunotherapy in CCA models, but early clinical trials combining MEKi with anti-PD-L1 therapy have yielded suboptimal results. Approach and Results: We hypothesized that the addition of a CD27 agonist would salvage MEKi-induced T cell impairment and reduce CCA burden in vivo. We show that CD27 agonism potentiates T cell activation in the presence of MEKi in vitro. Further, triple therapy with CD27 agonist, anti-PD-L1, and MEKi elicits efficacy in a subcutaneous CCA model, accompanied by increases in tumor-infiltrating CD8 ⁺ T cells with memory phenotypes. Although triple therapy enhanced CD8 ⁺ T cell infiltration in mice with orthotopic CCA liver tumors, its impact on overall survival was less pronounced. Further investigation revealed that orthotopic CCA tumors harbored more CD11b ⁺ Gr-1 ⁺ cells when compared to either subcutaneous CCA tumors or to normal liver. Finally, in mice with orthotopic CCA tumors treated with triple therapy, depletion of Gr-1 ⁺ cells triggered severe toxicity, characterized by rapid weight loss and uncontrolled systemic and hepatic inflammation. Conclusions: These findings identify myeloid cells as key mediators of both immunotherapy resistance and toxicity in CCA, highlighting the critical importance of tumor site and use of physiologically relevant preclinical models when evaluating immunotherapy strategies.