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

Xue, Wei; Brentville, Victoria A.; Symonds, Peter; Cook, Katherine; Yagita, Hideo; Metheringham, Rachael L.; Durrant, Lindy

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.

Citation

Xue, W., Brentville, V. A., Symonds, P., Cook, K., Yagita, H., Metheringham, R. L., & Durrant, L. (in press). SCIB1, a huIgG1 antibody DNA vaccination, combined with PD-1 blockade induced efficient therapy of poorly immunogenic tumors. Oncotarget, 7(50), https://doi.org/10.18632/oncotarget.13070

• Journal Article Type: Article
• Acceptance Date: Sep 24, 2016
• Online Publication Date: Nov 4, 2016
• Deposit Date: Feb 15, 2018
• Publicly Available Date: Feb 15, 2018
• Journal: Oncotarget
• Electronic ISSN: 1949-2553
• Publisher: Impact Journals
• Peer Reviewed: Peer Reviewed
• Volume: 7
• Issue: 50
• DOI: https://doi.org/10.18632/oncotarget.13070
• Keywords: DNA vaccine; Fc targeting; PD-1 blockade; melanoma; tumor rejection
• Public URL: https://nottingham-repository.worktribe.com/output/830080
• Publisher URL: http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=13070&path[]=41414
• Contract Date: Feb 15, 2018