Oncotarget

Research Papers:

SCIB1, a huIgG1 antibody DNA vaccination, combined with PD-1 blockade induced efficient therapy of poorly immunogenic tumors

Wei Xue _, Victoria A. Brentville, Peter Symonds, Katherine W. Cook, Hideo Yagita, Rachael L. Metheringham and Lindy G. Durrant

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Oncotarget. 2016; 7:83088-83100. https://doi.org/10.18632/oncotarget.13070

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Abstract

Wei Xue1, Victoria A. Brentville1, Peter Symonds1, Katherine W. Cook1, Hideo Yagita2, Rachael L. Metheringham1, Lindy G. Durrant1,3

1Scancell Limited, Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, UK

2Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

3Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, UK

Correspondence to:

Lindy G. Durrant, email: lindy.durrant@nottingham.ac.uk

Keywords: Fc targeting, DNA vaccine, PD-1 blockade, melanoma, tumor rejection

Received: May 23, 2016     Accepted: September 24, 2016     Published: November 04, 2016

ABSTRACT

Purpose: We have previously shown that supraoptimal signaling of high avidity T cells leads to high expression of PD-1 and inhibition of proliferation. This study was designed to see if this effect could be mitigated by combining a vaccine that stimulates high avidity T cells with PD-1 blockade.

Experimental Design: We investigated the anti-tumor effect of a huIgG1 antibody DNA vaccine (SCIB1) and PD-1 blockade.

Results: Vaccination of HLA-DR4 transgenic mice with SCIB1 induced high frequency and avidity T cell responses that resulted in survival (40%) of mice with established B16F1-DR4 tumors. SCIB1 vaccination was associated with increased infiltration of CD4 and CD8 T cells within the tumor but was also associated with upregulation of PD-L1 within the tumor environment. PD-1 blockade also resulted in increased CD8 T cell infiltration and an anti-tumor response with 50% of mice showing long term survival. In line with our hypothesis that PD-1/PD-L1 signaling results in inhibition of proliferation of high avidity T cells at the tumor site, the combination of PD-1 blockade with vaccination, enhanced the number and proliferation of the CD8 tumor infiltrate. This resulted in a potent anti-tumor response with 80% survival of the mice.

Conclusions: There is a benefit in combining PD-1 blockade with vaccines that induce high avidity T cell responses and in particular with SCIB1.


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