Hailemichael et al. demonstrate that addition of gp100 peptide vaccine formulated in incomplete Freund’s adjuvant, but not other nonpersistent vaccine formulations, to GVAX/anti-CTLA-4 surprisingly sequestered both gp100-specific effector T cells (Teffs) and other tumor-specific Teffs at the vaccination site, diminishing tumor control. The persistent, localized antigen initially attracted gp100 Teffs that in turn recruited myeloid cells and Teffs of other specificities to the vaccination site via IFNγ, chemokine signaling, and upregulation of adhesion molecules.
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-gamma, 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.
Author Info: (1) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (2) Department of Microbiology, Immunology, and Cancer Biology,
Author Info: (1) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (2) Department of Microbiology, Immunology, and Cancer Biology, Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, Virginia, USA. (3) Department of Genitourinary Medical Oncology/Immunology and. (4) Department of Genitourinary Medical Oncology/Immunology and. (5) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (6) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (7) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (8) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (9) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (10) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (11) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (12) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (13) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (14) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (15) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (16) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (17) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA. (18) Department of Genitourinary Medical Oncology/Immunology and. (19) Department of Microbiology, Immunology, and Cancer Biology, Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, Virginia, USA. (20) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA.
