Abstract 4057: Measurement of myeloid derived suppressor cells (MDSC), T regulatory cells (Treg), CD8+ and CD4+T-cells, and cytokines/chemokines in patients with metastatic melanoma treated with pembrolizumab and propranolol
Authors: Gandhi Shipra , Pandey Manu , Attwood Kristopher M. , Allen Cheryl , Tario Joseph , Shu Shin La , Levis Maria , Stack Suzanne M. , Wallace Paul , Bogner Paul , Puzanov Igor , Bucsek Mark J. , Repasky Elizabeth , Ernstoff Marc S. 
Published: August 2019

Abstract
Introduction: Immunotherapy has recently emerged as the cornerstone of metastatic melanoma treatment. Monotherapy with PD1 inhibitors results in response rate (RR) ~30%, while RR with combination PD1 + CTLA-4 inhibitors is ~60% but associated with high-grade toxicities in 50% patients (pts). We have shown in a mouse model that adrenergic receptor signaling blockade with propranolol (PRO) enhances anti-tumor activity of PD1 inhibition. Thus, we designed a phase Ib/II clinical trial to improve the activity of pembrolizumab (P) by combination with PRO at different doses recruiting 3 pts at each dose (10, 20 & 30 mg BID).
Methods: 3 pts with metastatic melanoma were treated with P 200 mg every 3 weeks + PRO 10 mg BID. Biomarkers analysis were planned to identify PRO dose which should be tested in phase II. Blood samples were collected at baseline, day 8 & prior to each cycle. MDSC & its subtypes, Treg, CD8+ & CD4+ T cells & 29 cytokine/chemokines were measured at each time point. Ratios of CD8+/m-MDSC, CD8+/e-MDSC, CD8+/PMN-MDSC & CD8+/Treg were analyzed.
Results: Trend toward an increase in CD8+T cell & MDSC subsets with decrease in above ratios was observed. There was a significant time-effect of CD8+/ PMN-MDSC (p=0.039). The 6 and 30 wk levels were significantly lower than baseline (p=0.046; 0.008). The 30 wk value of CD8+T cell/m-MDSC was also significantly lower compared to baseline (p=0.037). There was a significant time-effect for IP-10 (p=0.007) where the expression increases from baseline, peaking around 3 wk (Table 1).
Conclusion: We see a decrease in CD8+ T cell/MDSC (all subtypes) & increase in IP-10 over time. The inverse relationship of high IP-10 with decreasing CD8+/MDSC & CD8+/Treg populations would suggest potential role of IFN-γ & trafficking of CD8+ T-cells into tumor/tissue. We plan to recruit more pts in the study to analyze these trends & confirm our findings.
Table 1VariablesBaseline1 week3 weeks6 weeks9 weeks12 weeks30 weeksp-valueCD8+T cell%/Eosinophilic(e)-MDSC%31.1±19.215.9±7.145.8±37.113.9±4.619.3±6.813.9±213±1.50.532CD8+T cell %/monocytic(m)-MDSC%290.4±287.25.8±2.18±3.37.2±4.24±1.56±2.92.5±1.10.170CD8+T cell%/Polymorphonuclear(PMN)-MDSC%3544.2±2900.3208.3±77.7485.6±368.7110.3±76.1231.9±116.4168.3±76.339.5±14.90.039CD8+ T cell%/Treg%8.3±3.25.8±1.76.8±2.46.9±1.97±26.5±1.97.1±0.20.65Interferon gamma induced protein-10(IP-10) pg/ml576.1±83.91009±295.11865±593.51464.7±400.31353.4±445.91307.2±357.8934.2±227.30.007
Citation Format: Shipra Gandhi, Manu Pandey, Kristopher M. Attwood, Cheryl Allen, Joseph Tario, Shin La Shu, Maria Levis, Suzanne M. Stack, Paul Wallace, Paul Bogner, Igor Puzanov, Mark J. Bucsek, Elizabeth Repasky, Marc S. Ernstoff. Measurement of myeloid derived suppressor cells (MDSC), T regulatory cells (Treg), CD8+ and CD4+T-cells, and cytokines/chemokines in patients with metastatic melanoma treated with pembrolizumab and propranolol [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4057.