Systemic And Intratumoral Immune Profiling In Metastatic Pancreatic Cancer Patients Who Received Front-Line Folfirinox And Were Treated With Combination Immunotherapy With Ctla-4 Blockade In The Maintenance Setting.

Background: Metastatic pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis with a 5-year survival rate of 10%. For patients with metastatic PDA who respond to but cannot tolerate multi-agent chemotherapy, such as FOLFIRINOX, beyond 4-6 months, the optimal approach is unknown. Few studies have evaluated immunotherapy in the maintenance setting for PDA. Previously, a phase 2 trial in advanced PDA showed the promise of a GM-CSF-secreting allogeneic pancreatic tumor cell-based vaccine (GVAX) with CTLA-4 inhibitor, ipilimumab (IPI) [1]. Here we describe the first clinical testing of GVAX + IPI in the maintenance setting for patients with metastatic PDA who had ongoing response or stable disease after front-line FOLFIRINOX and evaluation of immune cell changes within the peripheral blood and tumor. Methods: From 40 vaccinated patients, we obtained paired peripheral blood lymphocytes (PBLs) from 20 patients and metastatic PDA biopsies from 6 of these 20 patients at baseline and week 7 (after at least two doses of GVAX + IPI). Samples were stratified into “stable” or “progressive” cohorts based on disease status on first restaging scan. To profile peripheral immune responses to treatment, we performed mass cytometry (CyTOF) analysis using a T cell-focused panel on PBLs. To profile intratumoral immune responses, biopsies containing \u003e30% tumor cellularity were chosen for 10-plex multiplex immunohistochemistry with T cell and myeloid cell-focused panels allowing us to examine changes in immune cell subsets after GVAX + IPI. Results. GVAX + IPI led to noticeable changes in PBLs including increases in T helper and cytotoxic effector memory cells and decrease in naive cytotoxic T cells, regardless of disease status. Among co-inhibitory markers assayed on PBLs, GVAX + IPI upregulated TIM3 and PD-1 in most helper and cytotoxic T cells, while CTLA-4 was largely maintained. Interrogation of the metastatic tumor microenvironment at baseline and on-treatment revealed significant increases in CD8+ T cells and pro-inflammatory M1 macrophages and decrease in pro-tumor M2 macrophages. Based on the CD8+ T cell functional status, there were increases in late effector (EOMES-PD-1+) and memory (EOMES-PD-1-) CD8+ T cells in the metastatic tumor after immunotherapy. Conclusions: In summary, we have proposed a mechanism for our immunotherapy in the maintenance setting. GVAX may be inducing systemic and intratumoral activation of naive T cells to antigen-specific T cells and promoting a decrease in immunosuppressive cells in the metastatic PDA microenvironment. Meanwhile, IPI may be blocking CTLA-4, which improves priming of T cells, but also may be leading to upregulation of regulatory markers TIM3 and PD-1 on T cell subsets as a compensatory mechanism. This trial highlights the challenge to inducing effective anti-tumor immune responses in metastatic PDA with inducible counterregulatory mechanisms. These compensatory increases could provide targets for the next generation of studies. 1Le DT, et al. J Immunother. 2013 Citation Format: Annie A. Wu, Katherine M. Bever, Won Jin Ho, Elana J. Fertig, Nan Niu, Lei Zheng, Rose M. Parkinson, Jennifer N. Durham, Beth Onners, Anna K. Ferguson, Cara Wilt, Andrew H. Ko, Andrea Wang-Gillam, Daniel A. Laheru, Robert A. Anders, Elizabeth D. Thompson, Elizabeth A. Sugar, Elizabeth M. Jaffee, Dung T. Le. Systemic and intratumoral immune profiling in metastatic pancreatic cancer patients who received front-line FOLFIRINOX and were treated with combination immunotherapy with CTLA-4 blockade in the maintenance setting [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PR-004.