Abstract
PurposeWe 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 DesignWe investigated the anti-tumor effect of a huIgG1 antibody DNA vaccine (SCIB1) and PD-1 blockade.ResultsVaccination 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.ConclusionsThere is a benefit in combining PD-1 blockade with vaccines that induce high avidity T cell responses and in particular with SCIB1.
Highlights
Numerous studies have shown that PD-1/PDL1 pathway is a negative regulator of T cells and that blocking this pathway can lead to improved T cell immunity [1, 2]
There is a benefit in combining PD-1 blockade with vaccines that induce high avidity T cell responses and in particular with SCIB1
We have previously shown that insertion of CD8 epitopes TRP2 and CD4 epitopes from gp100 into human IgG1 antibody DNA vaccine (SCIB1) induces high frequency and avidity CD8 and CD4 T cell responses in mice [17] and melanoma patients [19]
Summary
Numerous studies have shown that PD-1/PDL1 pathway is a negative regulator of T cells and that blocking this pathway can lead to improved T cell immunity [1, 2]. Pembrolizumab has improved efficacy over Ipilimumab [8] and is approved second line treatment for melanoma. It is showing encouraging results in NSCLC [9], gastric cancer [10], bladder cancer [11], head and neck cancer [12], Hodgkin’s lymphoma [13] and triple negative breast cancer [14]. There is evidence that patients whose tumors express PD-L1 have a higher response rate, many PD-L1 negative patients respond This discrepancy may be related to “adaptive resistance” which stems from the observation that normal cells and most cell lines do not express PD-L1 unless it is induced by IFNγ.
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