Role of CD27 Agonist in Combination With PD-L1 and MEK Inhibition on Antitumor Effect and CD8+ T Cells: Expanding Immunotherapy Options in CCA

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 (Kras^G21D, 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

References

1. Ferrucci PF, Cocorocchio E, Bonomo G, et al. A new option for the treatment of intrahepatic cholangiocarcinoma: percutaneous hepatic perfusion with CHEMOSAT delivery system. Cells. 2021;10(1):70.
2. Ruggieri AN, Yarchoan M, Goyal S, et al. Combined MEK/PD-L1 inhibition alters peripheral cytokines and lymphocyte populations correlating with improved clinical outcomes in advanced biliary tract cancer. Clin Cancer Res. 2022;28(19):4336-4345.
3. Dennison L, Ruggieri A, Mohan A, et al. Context-dependent immunomodulatory effects of MEK inhibition are enhanced with T-cell agonist therapy. Cancer Immunol Res. 2021;9(10):1187-1201.
4. Bennett FJ, Warren EAK, Hammons JN, et al. Expanding immunotherapy options in cholangiocarcinoma: role of CD27 agonist in combination with PD-L1 and MEK inhibition on antitumor effect and CD8+ T cells. San Francisco, CA, & online: presented at ASCO Gastrointestinal Cancers Symposium; January 18-20, 2024: poster E5.