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Radiation and immunotherapy in iCCA
Although the immune cells have the ability to detect and eradicate aberrant cancer cells, cancer cells have
multiple mechanisms to evade immune cells. These mechanisms include adjusting the tumor’s environment
to suppress immune reactions through the expression of proteins, such as cytotoxic T-lymphocyte-
associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), and by suppressing MHC
expression. Immune checkpoint inhibitors (ICIs), which inhibit interactions between CTLA-4 or PD-1,
have demonstrated significant efficacy in treating various cancers. Pembrolizumab, an anti-PD-1 antibody,
is FDA-approved for patients with CCA deficient in mismatch repair proteins (dMMR) or with
microsatellite instability-high tumors (MSI-H) , and for those with a high tumor mutational burden
[91]
[92]
[93]
(TMB-H) (≥ 10 mut/Mb) . Notably, dMMR has been reported to occur in approximately 10% of iCCA ,
while the incidence of TMB-H is < 5% of iCCA . Furthermore, the TOPAZ-1 phase III study showed that
[94]
durvalumab, an anti-PD-L1 antibody in combination with cisplatin and gemcitabine, provided an OS
benefit, making this regimen an accepted alternative first-line treatment option for advanced-stage biliary
[13]
tract cancer in a biomarker-unselected population .
The combination of immunotherapy and radiation has shown promising results in many preclinical studies,
as it can potentially have a synergistic effect on treatment efficacy. By damaging cancer cells, radiation
stimulates the release of tumor-specific antigens that serve as signals, leading to the recognition by immune
cells and the activation of cytotoxic T-cells. Radiation can also modulate the tumor microenvironment,
potentially enhancing the recruitment and infiltration of immune cells. This concept is the rationale behind
the combination of radiation and immunotherapy to eliminate cancer cells .
[95]

Evidence in the literature on the combination of radiotherapy and ICIs in iCCA has been primarily limited
to case reports as summarized in Table 3. Liu et al. reported a case of a 68-year-old male with a low PD-L1
expression level, high MSI, and high TMB stage IV iCCA . Following six cycles of immunotherapy, there
[96]
was a favorable response in the primary liver and metastatic nodes; however, new lung metastases occurred.
Subsequently, the patient underwent radiotherapy for the liver and lung lesions, followed by continued
immunotherapy. As a result, a complete response was observed in both the primary tumor and all
metastatic sites. A similar result was reported by Zhao et al. in four patients with refractory advanced iCCA
[97]
or pCCA that were effectively managed with ani-PDL-1 antibody following or concurrent with SBRT . In
addition, one patient had a disease that was able to be converted from initially unresectable to resectable
after combined therapy.

Typically, ICIs provide more responses in patients with dMMR, MSI-H, TMB-H, and/or PD-L1 expression.
However, a case report of three advanced-stage or recurrent iCCA patients can benefit from
immunotherapy combined with SBRT, even with low TMB, MSS, MMR proficiency, and negative PD-L1
expression . It is possible that radiotherapy may enhance tumor-associated antigen presentation, T-cell
[98]
recognition, and PD-L1 expression in tumor cells that otherwise may not respond as well to ICI.

Ongoing studies examining the role of combined treatment are summarized in Table 4. The CORRECT trial
(NCT03898895), a phase II single-arm study, investigates the combination of RT with camrelizumab, an
anti-PD-1 antibody, in patients with unresectable primary or initial postoperative recurrent bile duct cancer
without distant metastasis. Another trial, NCT04866836, explores the efficacy and safety of tislelizumab, an
anti-PD-1 antibody, combined with RT as a secondary treatment for advanced biliary malignancies in
patients who previously received chemotherapy. Another phase I trial (NCT04708067) aims to examine the
safety and efficacy of bintrafusp alfa, a bifunctional fusion protein composing the monoclonal antibody
avelumab and TGF-beta, in combination with hypofractionated RT for patients with locally advanced or