Cancer vaccine formulation dictates synergy with CTLA-4 and PD-L1 checkpoint blockade therapy
Yared Hailemichael, … , Victor H. Engelhard, Willem W. Overwijk
Yared Hailemichael, … , Victor H. Engelhard, Willem W. Overwijk
Published February 26, 2018
Citation Information: J Clin Invest. 2018;128(4):1338-1354. https://doi.org/10.1172/JCI93303.
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Research Article Immunology

Cancer vaccine formulation dictates synergy with CTLA-4 and PD-L1 checkpoint blockade therapy

Abstract

Anticancer vaccination is a promising approach to increase the efficacy of cytotoxic T lymphocyte–associated protein 4 (CTLA-4) and programmed death ligand 1 (PD-L1) checkpoint blockade therapies. However, the landmark FDA registration trial for anti–CTLA-4 therapy (ipilimumab) revealed a complete lack of benefit of adding vaccination with gp100 peptide formulated in incomplete Freund’s adjuvant (IFA). Here, using a mouse model of melanoma, we found that gp100 vaccination induced gp100-specific effector T cells (Teffs), which dominantly forced trafficking of anti–CTLA-4–induced, non-gp100–specific Teffs away from the tumor, reducing tumor control. The inflamed vaccination site subsequently also sequestered and destroyed anti–CTLA-4–induced Teffs with specificities for tumor antigens other than gp100, reducing the antitumor efficacy of anti–CTLA-4 therapy. Mechanistically, Teffs at the vaccination site recruited inflammatory monocytes, which in turn attracted additional Teffs in a vicious cycle mediated by IFN-γ, CXCR3, ICAM-1, and CCL2, dependent on IFA formulation. In contrast, nonpersistent vaccine formulations based on dendritic cells, viral vectors, or water-soluble peptides potently synergized with checkpoint blockade of both CTLA-4 and PD-L1 and induced complete tumor regression, including in settings of primary resistance to dual checkpoint blockade. We conclude that cancer vaccine formulation can dominantly determine synergy, or lack thereof, with CTLA-4 and PD-L1 checkpoint blockade therapy for cancer.

Authors

Yared Hailemichael, Amber Woods, Tihui Fu, Qiuming He, Michael C. Nielsen, Farah Hasan, Jason Roszik, Zhilan Xiao, Christina Vianden, Hiep Khong, Manisha Singh, Meenu Sharma, Faisal Faak, Derek Moore, Zhimin Dai, Scott M. Anthony, Kimberly S. Schluns, Padmanee Sharma, Victor H. Engelhard, Willem W. Overwijk

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Figure 3

Exhaustion and apoptosis of sequestered anti–CTLA-4 activated CD8+ Teffs.

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Exhaustion and apoptosis of sequestered anti–CTLA-4 activated CD8+ Teffs...
(A) Gating strategy for naive, non–pmel-1 Teffs and pmel-1 Teffs from PBMCs (top). Mice bearing 3-day-old, s.c. B16 melanoma received CD90.1+ pmel-1 T cells, early anti–CTLA-4 therapy, and vaccination with control/IFA or hgp100/IFA. (B) Ki67 protein expression by naive CD8+ T cells, non–pmel-1 CD8+ Teffs, and pmel-1 CD8+ Teffs in PBMCs, VdLNs, and at the vaccination site 9 days after the start of therapy. pmel-1 histograms show T cells in a gp100/IFA setting. (C) PD-1/LAG-3 expression in Teffs from PBMCs, VdLNs, tumor site, and vaccination site. (D) TRP-2–specific CD8+ Teffs in VdLNs (top panel) and quantitation of IFN-γ+TNF-α+ TRP-2–specific CD8+ Teffs in PBMCs, tumor site, and vaccination site (bottom panel). (E) Fas expression on naive T cells, non–pmel-1 Teffs, and pmel-1 Teffs from VdLNs, spleen, tumor site, and at the vaccination site 9 days after the start of therapy. (F) Apoptotic cell death from VdLNs, spleen, and at the vaccination site of naive CD8+ T cells, non–pmel-1 CD8+ Teffs, and pmel-1 CD8+ Teffs 9 days after the start of therapy, as measured by flow cytometry of annexin V and 7-AAD staining. Plots are shown as mean ± SEM (n = 5, *P < 0.05 unpaired 2-tailed t test). Data shown are representative of 2 experiments.