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Page 12 of 20 Gim et al. Hepatoma Res 2023;9:51 https://dx.doi.org/10.20517/2394-5079.2023.90

Pembrolizumab, an immune checkpoint inhibitor targeting PD-1 receptors, was approved by the FDA for
[102]
the treatment of TMB-H tumors . The KEYNOTE-158 trial assessed pembrolizumab in TMB-H tumors
[103]
across various sites . The study revealed a 29% ORR (95%CI: 21%-39%). Additionally, 57% of participants
achieved a DOR lasting 12 months or longer, and 50% attained a DOR of 24 months or longer. Although
there were 63 BTC patients in the KEYNOTE-158 trial, none of them had high TMB. However, two out of
the 63 patients had objective responses.

Recent data from the phase II CheckMate-848 study (NCT03668119) demonstrated promising results using
nivolumab and ipilimumab in patients with previously treated advanced or metastatic TMB-H solid
tumors . The ORR was 35.5% (95%CI: 24.1%-47.8%) in the group with tissue TMB-H and 22.5% (95%CI:
[104]
13.9%-33.2%) in the group with blood TMB-H. Based on the above findings, the current NCCN guidelines
list nivolumab and ipilimumab combination therapy as frontline and subsequent-line treatment for TMB-H
BTCs, and pembrolizumab is listed as a subsequent-line treatment for TMB-H BTCs .
[21]

High microsatellite instability and mismatch repair deficient
Tumors with mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H) levels show
increased neoantigen production and CD8+ T cell infiltration . MSI-H/dMMR leads to difficulties in
[105]
repairing DNA replication errors, causing mutations. The MSI-H/dMMR is identified in about 2.06% of
iCCA patients .
[17]

Pembrolizumab has received full FDA approval for the treatment of adult and pediatric patients with
unresectable or metastatic MSI-H or dMMR solid tumors, who have progressed after prior treatment and
have limited alternative options . The approval is based on data from multiple trials, including
[106]
KEYNOTE-158 (NCT02628067), KEYNOTE-164 (NCT02460198), and KEYNOTE-051 (NCT02332668),
involving 504 patients with over 30 types of tumors. An integrated analysis of these studies revealed that, at
a median follow-up of 20.1 months, pembrolizumab achieved an ORR of 33.3% (95%CI: 29.2%-37.6%),
comprising a CR rate of 10.3% and a partial response rate of 23.0%. According to the NCCN guidelines,
pembrolizumab is currently listed as both a first-line and subsequent-line treatment option for MSI-H/
[21]
dMMR tumors .

Dostarlimab, another anti-PD-1 monoclonal antibody, was assessed in the phase I GARNET trial. This
study included 106 patients who had advanced solid tumors, and two of them had MSI-H/dMMR BTCs .
[107]
The trial showed that an ORR at 38.7% (95%CI: 29.4%-48.6%) in patients with dMMR and CR was around
7.5%. A median DOR was not reached with a median follow-up of 12.4 months. About 8.3% of patients
experienced at least one grade 3 or higher adverse event, with the most common being an elevated lipase
level. Based on this, the FDA approved dostarlimab for recurrent or advanced solid tumors with MSI-H/
dMMR, which have progressed after previous lines of therapy and do not qualify for suitable alternative
treatment options .
[108]
Adoptive immunotherapy
While immune checkpoint inhibitors have made notable progress, their effectiveness in treating BTC
remains unsatisfactory. Another promising approach in the field of BTC immunotherapy is Chimeric
Antigen Receptor (CAR) T-cell therapy, which is currently being evaluated. CAR T-cell therapy has
demonstrated exceptional efficacy in the treatment of hematologic cancers, having received regulatory
approval for conditions such as B-cell lymphoma. However, expanding the use of CAR T-cell treatment to
solid tumors, such as BTC, presents unique challenges due to these tumors' ability to exclude T cells from
the tumor microenvironment and avoid immune system recognition.