Journal article
Cancer vaccine formulation dictates synergy with CTLA-4 and PD-L1 checkpoint blockade therapy
The Journal of clinical investigation, Vol.128(4), pp.1338-1354
04/02/2018
DOI: 10.1172/JCI93303
PMCID: PMC5873868
PMID: 29480817
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.
Details
- Title: Subtitle
- Cancer vaccine formulation dictates synergy with CTLA-4 and PD-L1 checkpoint blockade therapy
- Creators
- Yared Hailemichael - The University of Texas MD Anderson Cancer CenterAmber Woods - University of VirginiaTihui Fu - Department of Genitourinary Medical Oncology/Immunology and.Qiuming He - Department of Genitourinary Medical Oncology/Immunology and.Michael C Nielsen - The University of Texas MD Anderson Cancer CenterFarah Hasan - The University of Texas MD Anderson Cancer CenterJason Roszik - The University of Texas MD Anderson Cancer CenterZhilan Xiao - The University of Texas MD Anderson Cancer CenterChristina Vianden - The University of Texas MD Anderson Cancer CenterHiep Khong - The University of Texas MD Anderson Cancer CenterManisha Singh - The University of Texas MD Anderson Cancer CenterMeenu Sharma - The University of Texas MD Anderson Cancer CenterFaisal Faak - The University of Texas MD Anderson Cancer CenterDerek Moore - The University of Texas MD Anderson Cancer CenterZhimin Dai - The University of Texas MD Anderson Cancer CenterScott M Anthony - The University of Texas MD Anderson Cancer CenterKimberly S Schluns - The University of Texas MD Anderson Cancer CenterPadmanee Sharma - Department of Genitourinary Medical Oncology/Immunology and.Victor H Engelhard - University of VirginiaWillem W Overwijk - The University of Texas MD Anderson Cancer Center
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.128(4), pp.1338-1354
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/JCI93303
- PMID
- 29480817
- PMCID
- PMC5873868
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Grant note
- RP140522 / ; P50 CA093459 / UT MD Anderson Cancer Center SPORE in Melanoma grant from NCI NA / NA
- Language
- English
- Date published
- 04/02/2018
- Academic Unit
- Pathology
- Record Identifier
- 9984185170502771
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