Abstract 5001: High dose IL-2 (HDIL-2) results in increased PD-1 expression on CD45RA-CCR7-CD8+ and CD45RA-CCR7-CD4+ T cells in melanoma patients

Abstract

Abstract Introduction: HDIL-2 is associated with long-term remissions in Stage IV melanoma in less than 10% of patients. We hypothesized that HDIL-2 alters the expression of PD-1 on T cell subsets in melanoma patients. Methods: Samples were collected after written consent under an IRB approved protocol. Peripheral blood was collected at baseline and serially post-treatment at 24, 48, 72, and 96 hours from 6 patients with advanced stage melanoma undergoing HDIL-2. All patients were treatment naïve with regards to anti-PD-1 and anti-CTLA4 therapies. PBMCs were isolated and underwent intracellular cytokine and extracellular receptor staining. Co-signaling molecule expression was analyzed via flow cytometry. Statistical analysis was performed using paired t tests via Prism 6.0e software. Results: HDIL-2 was associated with a preferential loss of effector memory (TEM; CD45RA-CCR7-) CD4+ and CD8+ T cells and a relative enrichment of naïve (CD45RA+CCR7+) CD4+ and CD8+ T cells in the blood during the first 3 days of treatment. On day 4, frequencies of CD4+ and CD8+ TEM had returned to baseline. Importantly, PD-1 expression was significantly increased on day 4 post-treatment on CD8+ TEM relative to baseline (22.1% +/- 13.2% on day 4 compared to 13.4% +/- 7.4% at baseline; p = 0.04). This finding was also true for CD4+ TEM (11.4% +/- 6.1% on day 4 compared to 6.1% +/- 3.7% at baseline, p = 0.04). PD-1 expression was not statistically different within the other CD4+ and CD8+ memory T cell subsets including: naïve, central memory (CD45RA-CCR7+), or TEMRA (CD45RA+CCR7-) lymphocytes. Conclusion: These results demonstrate that HDIL-2 is associated with an increase in expression of PD-1 on TEM cells in patients with advanced melanoma suggesting a possible mechanism contributing to the limited efficacy of HDIL-2 in most patients. It is known that TEM cells function by migrating to peripheral tissues, and that CD8+ TEM cells are found specifically in metastatic melanoma lesions. Importantly, our findings illustrate a potential synergistic effect between HDIL-2 and PD-1 blockade. Upregulation of PD-1 and the chronologic pattern in which its expression changes under the effects of HDIL-2 provide a mechanistic rationale for testing the combination of HDIL-2 and anti-PD-1 therapy in patients with advanced melanoma. Citation Format: Maggie L. Diller, Susan Maio, Cabell E. Eysmans, David Lawson, Keith A. Delman, Ragini R. Kudchadkar, Mandy L. Ford. High dose IL-2 (HDIL-2) results in increased PD-1 expression on CD45RA-CCR7-CD8+ and CD45RA-CCR7-CD4+ T cells in melanoma patients. [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 5001. doi:10.1158/1538-7445.AM2015-5001