Background To better understand the immune stimulatory mechanisms of Oncolytic virus (OV), we evaluated the circulating OV-specific T cell response in patients during the course of OV therapy. Patients with histologically confirmed advanced clear cell renal cell carcinoma, who were naïve or refractory to prior systemic treatment and who had no prior treatment with immune checkpoint inhibitors, were treated with 4 weekly intravenous infusions of Pexa-Vec at 1 × 109 plaque forming units starting at Day -7 plus Cemiplimab (350 mg every 3 weeks) from Day 1. Radiographic assessments per RECIST 1.1 were performed centrally every 9 weeks from Day 1. Peripheral blood mononuclear cells (PBMCs) were collected and cryopreserved at baseline and 29 days post initial Pexa-Vec treatment.
Methods We performed functional IFNγ ELISPOT analysis on longitudinal PBMC samples using a custom panel of OV epitopes and culture conditions designed to measure existing OV-specific memory T cell cytolytic activity . PBMC samples were tested for IFNγ release following stimulation with OV peptides using two different assay conditions: 1) measurement following direct ex vivo stimulation with OV peptides alone, and 2) measurement following 10 days of T cell expansion in the presence of OV peptides, T cell supportive cytokines (GM-CSF, IL-4, IL-7 and IL-15), and autologous dendritic cells. The number of OV-specific IFNγ spots was correlated with the clinical response and tumor regression.
Results In preliminary analyses, 8 of the 11 (72.7%) patients showed tumor burden reduction, 4 of whom had ≥30% confirmed reduction that qualify as RECIST1.1 PRs (figure 1 and 2). OV-specific IFNγ+ T cells were detected in only 3 out of 11 patients in the non-expanded ELISPOT culture conditions (figure 3A), but in 8 out of 11 patients when T cells were first expanded for 10 days in the presence of OV peptides prior to ELISPOT, which trended toward a correlation with the preliminary clinical response assessment (figure 3B). Prolonged stimulation with CMV, EBV and Influenza peptides did not show any correlation (R2 = 0.005), suggesting that the treatment and culture expansion influenced relevant OV-specific memory T cell proliferation.
Conclusions These results suggest that OV-specific T cell responses can be induced by OV therapy. In addition, 10-day expansion of low levels of OV-specific circulating T cells can amplify signals in ELISPOT analysis and might enable systemic tracking of patient responses in blood samples collected at early time points. The observed CD8+ T cell response to oncolytic vaccinia virus in patients supports the rationale for combination treatment with Pexa-Vec and immune checkpoint inhibitors.
Acknowledgements Sun Young Rha, Yonsei Cancer Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of KoreaJamie Merchan, University of Miami Health System, Miami, FL, USASung Yong Oh, Dong-A University Hospital, Busan, Republic of KoreaChan Kim, Cha University Bundang Medical Center, Seongnam, Republic of KoreaWoo Kyun Bae, Chonnam National University Hwasun Hospital, Hwasun, Republic of KoreaHyun Woo Lee, Ajou University Hospital, Suwon, Republic of Korea.
Trial Registration NCT03294083
Ethics Approval The study was approved by University of Miami Institutional Reivew Board, approval number 20180055.
Dillon M, Jeong S, De Silva N, et al. Tracking oncolytic virus-specific CD8+ T cells with epitope-based, HLA-agnostic peptides in a renal cell carcinoma clinical trial. CRI-CIMT-EATI-AACR INTERNATIONAL CANCER IMMUNOTHERAPY CONFERENCE 2019. Abstract #A067
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