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.
View: Text | PDF
Research Article Immunology Article has an altmetric score of 24

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

×

Figure 4

CXCR3 is required for CD8+ Teff localization to tumor.

Options: View larger image (or click on image) Download as PowerPoint
CXCR3 is required for CD8+ Teff localization to tumor. (A) Experimental ...
(A) Experimental scheme. Mice bearing 3-day-old, s.c. B16-BL6 melanomas received naive pmel-1 T cells and early anti–CTLA-4 therapy or vaccination with hgp100 in IFA. (B) Chemokine receptor expression on naive CD8+ T cells, pmel-1 CD8+ Teffs, and non–pmel-1 CD8+ Teffs in blood 9 days after vaccination. (C) Mice bearing 3-day-old, s.c. B16-BL6 melanomas received pmel-1 T cells and early anti–CTLA-4 therapy or vaccination with hgp100/IFA or control/IFA. Cytokine and chemokine concentrations in supernatant from tumor and vaccination site homogenates 9 days after vaccination. All data shown are mean ± SEM and are representative of 3 experiments (n = 5 mice per group, *P < 0.05 determined by unpaired 2-tailed t test). (D and E) Mice bearing 3-day-old, s.c. B16-BL6 melanomas received naive pmel-1 T cells and early anti–CTLA-4 therapy or vaccination with hgp100 in IFA (s.c.) or anti-CXCR3 (i.p.) or IgG therapy (i.p.) on days 3, 5, 7, 9, and 11 after tumor injection. (D) Kaplan-Meier survival curves. (E) Absolute number of non–pmel-1 and pmel-1 T cells (mean ± SEM, n = 5) at the tumor and vaccination sites (mean ± SEM, n = 5) analyzed 9 days after the start of CXCR3 blockade. Data shown are representative of 3 experiments. (F) CXCL9 and CXCL10 mRNA expressions by RNA sequencing and overall patient survival obtained from public TCGA repositories (https://tcga-data.nci.nih.gov and http://gdac.broadinstitute.org/). Bars show mean ± SEM CD8 mRNA level as determined by paired 2-tailed t test.