Immunotherapy has changed the treatment paradigm of several cancers, including biliary tract cancers (BTCs). Based on results of the TOPAZ-1 trial, immune checkpoint inhibition with PD-L1 blockade (durvalumab) plus chemotherapy (gemcitabine/cisplatin) is a validated and preferred first-line treatment for advanced or metastatic BTCs, including cholangiocarcinoma (CCA).1 However, acquired tumor resistance in the subset of BTCs that initially respond to immunotherapy is a clinical concern, and CCA harbors redundant mechanisms of resistance to immunotherapy and immune checkpoints. Therefore, better understanding of dominant mechanisms of resistance and immune suppression, and ultimately, novel immunotherapy strategies that can overcome these resistance mechanisms are needed. At the 5th annual CCA Summit meeting, Gregory Lesinski, PhD, MPH, discussed novel immunotherapy targets in BTC.2
Immunotherapy is an area of active research in BTC; several immunotherapy approaches are currently being investigated, including immune checkpoint inhibitors that block immune-suppressing signals with or without other active agents, immune-stimulating agonists (eg, CD27), adoptive T-cell therapy that consists of modified T cells that target tumor components (chimeric antigen receptor T-cell therapy), and cancer vaccines.2 Based on the hypothesis that MEK inhibition enhances responses to PD-L1 inhibition, the randomized, phase 2 NCI 10139 trial (NCT03201458) evaluated the combination of atezolizumab and the MEK inhibitor cobimetinib versus atezolizumab alone in patients with metastatic BTC following first-line chemotherapy. Preliminary results show that the combination therapy led to significant prolongation of progression-free survival (PFS) compared with immunotherapy alone (median PFS 111 days vs 57 days, respectively; P =.0268).3
However, MEK inhibition is thought to have detrimental effects on host T-cell activation, and the addition of immune-stimulating agonists may be needed to rescue T-cell function. In this context, CD27 may represent an immune-stimulating agonist of choice given that it is selectively upregulated by MEK inhibitors in tumor-infiltrating lymphocytes and is expressed in all stages of T-cell maturation.2 Therefore, it was hypothesized that the addition of a CD27 agonist to the combination PD-L1 and MEK inhibition may further improve clinical outcomes via tumor microenvironment (TME) immunomodulation. Based on this rationale, a randomized phase 2 study (NCI 10476; NCT04941287) is evaluating the safety and antitumor activity of atezolizumab plus the CD27 immune agonist CDX-1127 (varlilumab) with or without addition of cobimetinib in previously treated unresectable BTCs.2 Eligible patients may have received durvalumab and gemcitabine/cisplatin and/or prior FGFR2/IDH1-targeted therapy.
Several novel and alternative immunotherapy strategies are being explored in CCA. The potential role of personalized immunotherapy in BTC is unknown, but genomic analysis may identify subtype-specific immune signatures and novel personalized immunotherapy targets.2 Adoptive cell therapy may represent another viable immunotherapy approach for patients with CCA.2 Other areas of research include identification of inhibitory or agonistic immune checkpoints that are more selectively tailored to the biology of CCA, development of myeloid- or stroma-targeted agents that could effectively overcome the immune-suppressive TME, and whether oncolytic virotherapy or innate immune-targeted agents (ie, natural killer cells) can be leveraged in CCA. Although several such exciting avenues exist, further research is warranted to define the role of immunotherapy in patients with CCA.
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