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

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

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1338-1354
Number of pages17
JournalJournal of Clinical Investigation
Volume128
Issue number4
DOIs
StatePublished - Apr 2 2018

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Cancer Vaccines
Cytotoxic T-Lymphocytes
Ligands
Vaccination
Proteins
Therapeutics
Neoplasms
Peptides
Neoplasm Antigens
Intercellular Adhesion Molecule-1
Dendritic Cells
Monocytes
Melanoma
Vaccines
T-Lymphocytes
Thomsen-Friedenreich antibodies
Water

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cancer vaccine formulation dictates synergy with CTLA-4 and PD-L1 checkpoint blockade therapy. / Hailemichael, Yared; Woods, Amber; Fu, Tihui; He, Qiuming; Nielsen, Michael C.; Hasan, Farah; Roszik, Jason; Xiao, Zhilan; Vianden, Christina; Khong, Hiep; Singh, Manisha; Sharma, Meenu; Faak, Faisal; Moore, Derek; Dai, Zhimin; Anthony, Scott M.; Schluns, Kimberly S.; Sharma, Padmanee; Engelhard, Victor H.; Overwijk, Willem W.

In: Journal of Clinical Investigation, Vol. 128, No. 4, 02.04.2018, p. 1338-1354.

Research output: Contribution to journalArticle

Hailemichael, Y, Woods, A, Fu, T, He, Q, Nielsen, MC, Hasan, F, Roszik, J, Xiao, Z, Vianden, C, Khong, H, Singh, M, Sharma, M, Faak, F, Moore, D, Dai, Z, Anthony, SM, Schluns, KS, Sharma, P, Engelhard, VH & Overwijk, WW 2018, 'Cancer vaccine formulation dictates synergy with CTLA-4 and PD-L1 checkpoint blockade therapy', Journal of Clinical Investigation, vol. 128, no. 4, pp. 1338-1354. https://doi.org/10.1172/JCI93303
Hailemichael, Yared ; Woods, Amber ; Fu, Tihui ; He, Qiuming ; Nielsen, Michael C. ; Hasan, Farah ; Roszik, Jason ; Xiao, Zhilan ; Vianden, Christina ; Khong, Hiep ; Singh, Manisha ; Sharma, Meenu ; Faak, Faisal ; Moore, Derek ; Dai, Zhimin ; Anthony, Scott M. ; Schluns, Kimberly S. ; Sharma, Padmanee ; Engelhard, Victor H. ; Overwijk, Willem W. / Cancer vaccine formulation dictates synergy with CTLA-4 and PD-L1 checkpoint blockade therapy. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 4. pp. 1338-1354.
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AU - Nielsen, Michael C.

AU - Hasan, Farah

AU - Roszik, Jason

AU - Xiao, Zhilan

AU - Vianden, Christina

AU - Khong, Hiep

AU - Singh, Manisha

AU - Sharma, Meenu

AU - Faak, Faisal

AU - Moore, Derek

AU - Dai, Zhimin

AU - Anthony, Scott M.

AU - Schluns, Kimberly S.

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AU - Engelhard, Victor H.

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