BackgroundProstate cancer (PC) is the most common non-cutaneous diagnosed cancer among men in USA.1 Although clinical outcomes are favorable for patients with localized disease, 20–30% of patients will develop metastatic prostate cancer (mPC) and have poor prognosis. Immunotherapy, as a single agent, provides benefit to a small subset of PC patients, which is thought to be partially due to its known cold tumor immune microenvironment (TIME). Combination studies are needed to enhance benefit.2 Prostvac is a therapeutic cancer vaccine engineered to activate an immune response against prostate-specific Antigen (PSA).3 Prostvac alone could induce systemic immune response by increasing immune-cell infiltrates in and around the tumor.4 In this study, we are exploring the effect of Prostvac in combination with nivolumab in TIME in prostate cancer.MethodsWe treated locally advanced prostate cancer patients (n=6) undergoing radical prostatectomy (RP) with neoadjuvant Prostvac in combination with nivolumab, an immune checkpoint PD-1 inhibitor. Dynamic changes in TIME before and after treatment were studied using multiplex immunofluorescence (Opal Method). Formalin fixed paraffin-embedded sections from matched pre-treated prostate biopsies and post-treated RP samples were stained with a validated T cell panel (DAPI, CD4, CD8, FOXP3, Ki67, Pan CK and PD-L1). To analyze the data, TIME was segmented into 3 compartments: intratumoral, invasive margin and benign.ResultsCombination immunotherapy significantly increased CD4+ T cell density in the invasive margin (mean 211.5 cells/mm2 vs 592.2 cells/mm2, p<0.05), with similar trend in the intratumoral and the benign compartments. CD8+ T cell density increased after treatment in the invasive margin (mean 47.25 cells/mm2 vs 157cells/mm2) and the benign compartment. 5/6 and 4/6 patients showed more than 2-fold increase of CD4 and CD8 T cells in the TIME, respectively, in at least one of the three compartments. Increased proliferative indices in CD4+ and CD8+ T cells were also seen after treatment. Tregs were present in low frequencies in TIME (maximum of 12 cells/mm2) with no significant changes. Moreover, a significant drop in tumor cell Ki67 after treatment (mean 252.8 cells/mm2 vs 100.5 cells/332, p<0.05) suggests that the combination may control tumor growth.ConclusionsThe combination of Neoadjuvant Prostvac and nivolumab was associated with increased immune cell infiltration in a cohort of early prostate cancer patients. A broader examination of the TIME and the role immune cells undertake to control tumor growth is on-going.Trial RegistrationNCT02933255ReferencesSiegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin (Internet) 2020;70:7–3Zhao SG, Lehrer J, Chang SL, et al. The immune landscape of prostate cancer and nomination of PD-L2 as a potential therapeutic target. J Natl Cancer Inst 2018;111:301–10.Madan RA, Arlen PM, Mohebtash M, et al. Prostvac-VF: a vectorbased vaccine targeting PSA in prostate cancer. Expert Opin Investig Drugs 2009;18:1001–11Abdul Sater H, Marté JL, Donahue RN, et al. Neoadjuvant PROSTVAC prior to radical prostatectomy enhances T-cell infiltration into the tumor immune microenvironment in men with prostate cancer. J Immunother Cancer 2020;8(1):655–64Ethics ApprovalThis study was performed in compliance with ethical standard and was approved by the NIH IRB, 17C-0007. All patients participating in this study gave an informed consent before taking part.
Analysis of N6-Methyladenosine Modification Patterns and Tumor Immune Microenvironment in Pancreatic Adenocarcinoma
