Abstract A05: Pharmacodynamics of immune checkpoint blockade therapy indicate drivers of response
Authors: Grasso Catherine S. , Tsoi Jennifer , Abril-Rodriguez Gabriel , Quist Michael J. , Ross-MacDonald Petra , Wind-Rotolo Megan , Ribas Antoni 
Published: June 2021

Abstract
To identify drivers of response and resistance we analyzed RNA-seq data from biopsies of 78 patients (pts) enrolled in the BMS 038 clinical trial. Pts with metastatic melanoma had biopsies at baseline and on treatment while receiving immune checkpoint blockade therapy, either nivolumab single agent (N = 23 after ipilimumab progression, N = 24 ipilimumab-naive) or combination ipilimumab and nivolumab (N = 28). In the combined data set, there were 28 pts with progressive disease (PD), 18 with stable disease (SD) and 25 with complete or partial response (CRPR). We used Microenvironment Cell Populations (MCP)-Counter to perform RNA deconvolution to assess levels of immune cell infiltration in each sample. T-cell infiltration was significantly higher in CRPR at baseline relative to PD (p-value &lt; 0.007 consistent with previous observations (Tumeh et al., Nature 2014). In CRPR, T-cell infiltration increased significantly on treatment relative to baseline (p-value &lt; 0.000427) as expected. Surprisingly, T-cell infiltration also increased in on-treatment biopsies in both SD (p-value &lt; 0.003) and PD (p-value &lt; 0.0182), although the increase was lower than in CRPR. These data indicate that even without clinically observable response, there is pharmacodynamic evidence of activity. In addition to changes in the tumor microenvironment, samples exhibited tumor-specific changes in gene expression with the potential to impact response to immune blockade therapy. Wnt signaling is a mechanism of immune exclusion as a result of β-catenin suppressing the expression of chemokines necessary to attract dendritic cells key for full immune infiltration. In our cohort, Wnt signaling levels did not differ significantly before anti-PD1 therapy; however, only responders showed a significant decrease in Wnt signaling (p-value &lt; 0.003) on treatment, with a concomitant decrease in the Wnt target gene MYC, which is immunosuppressive in addition to driving tumor cell proliferation. In addition, consistent with the previously reported role of Wnt signaling in suppressing dendritic cell infiltration, responding biopsies showed a significant increase in dendritic cells (p-value &lt; 0.013) on treatment. Importantly, dendritic cells only significantly increased in biopsies of responding pts on combination therapy (p-value = 0.004). The increase in dendritic cells in the combination therapy, likely the result of the increased T cells at the tumor site released by removing the anti-CTLA4 immune blockade using ipilimumab, has the potential to explain the increased overall immune response in these cases. Together these data indicate that most tumors exhibit an immune response to immune blockade therapy, whether or not it results in a clinical response, and that clinical response to immune blockade therapy has decreased Wnt signaling and increase in dendritic cells. Our findings imply that interventions bringing T cells and dendritic cells into the tumor and inhibiting Wnt signaling should be a focus of combination therapeutic efforts.
Note: This abstract was not presented at the conference.
Citation Format: Catherine S. Grasso, Jennifer Tsoi, Gabriel Abril-Rodriguez, Michael J. Quist, Petra Ross-MacDonald, Megan Wind-Rotolo, Antoni Ribas. Pharmacodynamics of immune checkpoint blockade therapy indicate drivers of response [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A05.