Abstract 2485: A combined mregDC and Treg signature associates with antitumor efficacy of CCR4 antagonist tivumecirnon FLX475
Authors: Grant Adam , Adamik Juraj , Qiu Jingtao , Wert Jacob , Grandcolas Molly , Jacobson Scott , Goyal Rakesh K. , Ho William , Ikeda Shoji , Au Marvin , Trujillo Damian , Chisamore Michael , Nagata Denise de Almeida , Ghomi Mohsen S. , Brockstedt Dirk G. , Kassner Paul D. , Katibah George 
Published: March 2024

Abstract
Cancers evade immune surveillance through multiple mechanisms including the recruitment of immunosuppressive regulatory T cells (Treg). Tivumecirnon (formerly known as FLX475), a small molecule oral CCR4 antagonist under clinical evaluation, blocks the binding of CCR4 to its ligands CCL17 and CCL22 and thereby reduces Treg infiltration into the tumor microenvironment (TME). This relieves Treg-mediated immune suppression resulting in increased antitumor immunity. Our clinical study (NCT03674567) demonstrated that tivumecirnon can block the local accumulation of Treg in the TME and has clinical activity as monotherapy as well as in combination with pembrolizumab. In both mouse and human tumors, we identified a subset of tumor infiltrating dendritic cells (DC) producing high levels of CCL22, previously identified as mregDC, suggesting a potential role in the CCR4-dependent recruitment of Treg.
To study the role of mregDC in the recruitment of Treg, non-clinical studies were performed. CD45+ immune cells from the TME of MB49 tumor bearing mice treated with tivumecirnon or vehicle and were analyzed by flow cytometry, scRNA-seq and CITE-seq. We confirmed that mregDC cells are the primary producer of CCL22 in the TME and that tivumecirnon treatment reduced the number of Treg cells in the TME and increased the percentage of IFN gamma and granzyme B expressing CD4+ T cells.
Based on these findings we interrogated tumor biopsies from patients from our clinical study prior to (n = 33), and after approximately 6 weeks of treatment (n = 22, pre/post-treatment paired samples) with tivumecirnon +/- pembrolizumab. We performed RNAseq and compared to published biopsy data from anti-PD-1 treated patients. We found that higher mregDC + Treg signature levels at baseline significantly (p &lt; 0.001) associated with response to tivumecirnon and pembrolizumab therapy. Importantly, analysis of published datasets revealed that higher baseline mregDC and Treg levels are not associated with response to anti-PD-1 monotherapy. Analysis of TCGA gene expression data demonstrated a positive correlation with mregDC and Treg cells across human tumor types, indicating a previously unknown relationship between these cell types. Further application of this mregDC and Treg signature to the TCGA dataset identified a subset of cancer types resistant to prior treatments that could potentially benefit from combinatorial treatment with tivumecirnon. Overall, this study demonstrated that inhibition of the CCR4 pathway using tivumecirnon can disrupt the immunosuppressive mregDC – Treg axis leading to enhanced antitumor activity. Furthermore, the levels of mregDC and Treg may be used as a biomarker for selection of patients more likely to respond to tivumecirnon in combination with anti-PD-1. Additional studies are required to confirm these results
Citation Format: Adam Grant, Juraj Adamik, Jingtao Qiu, Jacob Wert, Molly Grandcolas, Scott Jacobson, Rakesh K. Goyal, William Ho, Shoji Ikeda, Marvin Au, Damian Trujillo, Michael Chisamore, Denise de Almeida Nagata, Mohsen S. Ghomi, Dirk G. Brockstedt, Paul D. Kassner, George Katibah. A combined mregDC and Treg signature associates with antitumor efficacy of CCR4 antagonist tivumecirnon FLX475 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2485.