Abstract 243: Expression of T-cell checkpoint ligands on circulating tumor cells is modulated following treatment of patients with an anti-tumor DNA vaccine

Abstract

Abstract Background: We have previously demonstrated in a murine tumor model that treatment with a DNA vaccine could lead to increased PD-1 expression on antigen-specific CD8+ T cells, led to upregulated levels of PD-L1 on tumors, and that the anti-tumor efficacy of the vaccine was enhanced when combined with PD-1/L1 blockade. We therefore examined whether prostate cancer patients previously treated with a DNA vaccine similarly upregulated these immunosuppresive ligands on their tumor cells, or the corresponding receptors on tumor-specific CD8+ T cells, and if augmented Th1-type immune responses were detectable following in vitro stimulation with checkpoint blockade. Methods: Circulating tumor cells (CTCs, CD45-/EpCAM+) from 16 prostate cancer patients with castrate-resistant disease, and antigen-specific (tetramer+) CD8+ T cells from those patients that were HLA-A2+ (6/16), were analyzed for their expression of various checkpoint ligands (PD-L1, galectin-9, HVEM) or receptors (PD-1, TIM-3, LAG-3, BTLA, CD160) using flow cytometry before and after treatment with a DNA vaccine encoding prostatic acid phosphatase (PAP). Immune responses to the PAP target antigen were measured in vitro for cytokine secretion via ELISA, or by a trans-vivo DTH-footpad assay, in the presence or absence of PD-1/L1 blockade. Results: Patients that developed either long-term immune responses or changes in PSA doubling time following vaccination had significantly higher levels of PD-L1 and HVEM, and lower levels of galectin-9, on their post-treatment CTCs than patients who did not develop responses. No significant changes in PD-1 or other regulatory receptors were detectable on tetramer+ CD8+ T cells. However, at least 25% of patients following immunization had augmented PAP-specific cytokine secretion in vitro when combined with PD-L1 blockade. PD-1 regulated PAP-specific responses were also observed in patients using the trans vivo DTH assay. Conclusions: These results demonstrate that the development of an anti-tumor immune response via DNA vaccination can lead to changes in checkpoint ligand expression on tumor cells and checkpoint-regulated immune responses. This suggests that combining DNA vaccines with blockade of one or more of these checkpoint pathways could produce enhanced anti-tumor responses in patients with prostate cancer. Citation Format: Brian T. Rekoske, Brian M. Olson, Douglas G. McNeel. Expression of T-cell checkpoint ligands on circulating tumor cells is modulated following treatment of patients with an anti-tumor DNA vaccine. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 243. doi:10.1158/1538-7445.AM2015-243