There is an unmet need for novel therapies for unresectable cholangiocarcinoma (CCA) despite the addition of programmed death-ligand 1 (PD-L1) therapy to the standard of care.
A recent phase 2 trial of dual PD-L1 inhibition (PD-L1i) plus mitogen-activated protein kinase inhibition (MEKi) demonstrated significant improvement in progression-free survival in patients with advanced biliary tract cancer.1,2
MEKi enhances tumor antigen presentation and T-cell tumor infiltration and impairs T-cell priming and activation. Moreover, adding a differentiation 27 agonist (CD27Ag) cluster effectively restores T-cell activation hindered by MEKi-induced impairment and fosters T-stem–like and resident memory phenotypes.3,4
Frances J. Bennett, MD, presented study results at ASCO GI. The study aimed to determine if adding a CD27Ag to MEKi plus PD-L1i combination therapy would salvage MEKi-induced impairment of T-cell activation and cultivate an improved antitumor response.
Pmel-1 mice were utilized to extract immune cells, subsequently stimulated with glycoprotein 100. These cells were then cultivated in a controlled environment with 100 IU/mL interleukin-2, with single, dual, or triple therapy involving CD27Ag, cobimetinib (MEKi), and/or αPD-L1.
Day 3 flow cytometry was used to characterize CD8+ T-cell phenotype and cytokine expression. Additionally, syngeneic murine CCA cell line URCCA4.3 (KrasG21D, tp53–/–) were injected into C57BL/6 mice, subcutaneously or intrahepatically, followed by approximately 3 weeks of treatment with single, dual, or triple therapy.
For CD8 depletion studies, the CD8-depleting antibody was administered 1 day before and after the surgery, with additional doses given every 3 to 4 days after that.
Flow cytometry was used to analyze the lymphocytes obtained from the tumor and tumor-draining lymph nodes, which were harvested at the end of the study.
MEKi, alone or in combination with αPD-L1, reduced the frequency of activated T cells in vitro (dose-dependent effect on CD69+). CD27Ag, in combination with MEKi, effectively sustained robust T-cell activation.
Triple-therapy combination PD-L1i/MEKi/CD27Ag significantly reduced the mouse tumor growth rate compared with single or dual therapies (P<.05). Tumor-infiltrating lymphocytes comprised a stem-like memory (Tcf-1+), effector memory (CD44+ CD62L–), and tissue-resident memory (CD103+ CD69+) phenotype in triple therapy versus single or dual therapy (P<.01, P<.0001, and P<.0001, respectively).
All groups exhibited comparable CD8+ stem-like cells (Tcf-1+ Tim-3–) in the draining lymph nodes.
However, these cells were exclusively detected in the tumor samples from the triple-therapy group (P<.05). Cell depletion experiments demonstrated that the presence of CD8+ T cells was essential for triple therapy in vivo.
In the triple-therapy mice group, an aggressive orthotopic liver tumor model demonstrated a significant increase in median overall survival compared with the control group (37.5 days vs 29.5 days; P<.01).
The results of this study demonstrated that MEKi-mediated impairment of T-cell activation was prevented by CD27 agonism. In addition, this triplet therapy increased the trafficking of T cells with stem-like, effector, or resident memory properties, resulting in enhanced antitumor responses.
In an ongoing phase 2 clinical trial, this therapy is evaluated in patients with metastatic CCA.4
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