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Background Oncolytic viruses have great potential as an immunotherapy modality in melanoma. 1 However, the combination of the oncolytic virus Talimogene Laherparapvec (TVEC) with immune checkpoint blockade did not improve the progression-free or overall survival in melanoma patients.2 Likewise, localized treatment with TVEC has rarely been reported to affect distant metastases (i.e., an abscopal effect).3 Because of these disappointing clinical results, we sought to understand how oncolytic virus treatment induces antigen presentation and antigen-specific T cell responses - important steps in the development of an efficient immune response against both primary and metastatic disease.Methods B16F10(+/-OVA) and YUMMER1.7 mouse models of melanoma were assessed by flow cytometry for antigen presentation and development of antigen-specific T cells after either H1N1 (B16F10) or HSV (YUMMER1.7) delivery. Human peripheral blood lymphocytes from melanoma patients before and after TVEC treatment were stimulated ex vivo with virus, tumor antigen, or vehicle and assessed by flow cytometry.Results Injecting mouse models of melanoma with oncolytic virus revealed that antigen presentation was significantly enhanced compared to vehicle-injected controls, indicating functional antigen processing and presentation. After oncolytic virus injection, a viral antigen-specific, but not tumor antigen-specific, T cell response developed within both the tumor and peripheral blood of these animals ( figure 1). These cells were granzyme B, PD1, and Tcf1 positive, indicating a functional response. Further, we evaluated the ability of peripheral blood lymphocytes from melanoma patients to response to viral or tumor antigen ex vivo before and after treatment with TVEC. Lymphocytes from virus-treated hosts that were stimulated with viral antigen ex vivo produced more IL2 and granzyme B compared with virus-naive lymphocytes; this effect was not seen when the cells were exposed ex vivo to tumor antigen (figure 2). This indicates the presence of T cell effector responses to the oncolytic virus, but not the tumor, in these patients.Conclusions Overall, our data show that despite functional antigen presentation machinery, delivery of an oncolytic virus induces a dominant antigen-specific T cell response against viral antigen rather than tumor antigen. This is true across two models of melanoma and two different viruses in mice, and is supported by ex vivo studies in human peripheral blood lymphocytes. These data provide one explanation for the failure of oncolytic viruses to induce an abscopal effect, as only cells infected by the virus are targeted. These data also provide an explanation for the inability of TVEC to improve responses to systemic immunotherapy.Acknowledgements We thank Jessalyn Ubellacker for the kind gift of the YUMMER1.7 cells; Peigen Huang, Anna Khachatryan, and Mark Duquette for technical assistance. We additionally thank the NIH Tetramer Core for the tetramers used in this study, and the MGH Pathology Flow Core for use of their facilities.References Andtbacka RHI, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS. Talimogene laherparepvec improves durable respose rate in patients with advanced melanoma. J Clin Oncol. 2015;33(25):2780–8.Chesney JA, Ribas A, Long GV, Kirkwood JM, Dummer R, Puzanov I, Hoeller C, Gajewski TF, Rutkowski P, Demidov L, Arenberger P, Shin SJ, Ferrucci PF, Haydon A, Hyngstrom J, van Thienen JV, Haferkamp S, Malvehy Guilera J, Rapoport BL, VanderWalde A, Diesde SJ, Anderson JR, Triechel S, Chan EL, Bhatta S, Gansert J, Hodi FS, Gogas H. Randomized, double-blind, placebo-controlled, global phase III trial of talimogene laherparepvec combined with pembrolizumab for advanced melanoma. J Clin Oncol. 2022;41:3.Sierra-Davidson K, Dedeila A, Lawless A, Sharova T, Kaufman HL, Boland GM, Cohen S. Genetic factors associated with clinical response in melanoma patients treated with talimogene laherparapvec: a single-institution retrospective analysis. Ann Surg Oncol. 2025;32(1):482–494.Ethics Approval This study was approved by the Massachusetts General Hospital (MGH) Institutional Animal Care and Use Committee; protocol number 2011N000085. This study was approved by MGH’s Institutional Review Board; protocol number DFHCC 11-181.Abstract 895 Figure 1Frequency of T cells in YUMMER1.7-bearing animals that are virus (HSV) or tumor (gp100) antigen-specific after treatment with HSV. * indicates significance by two-way ANOVA with Tukey’s post-hoc test, n=8 animalsAbstract 895 Figure 2Frequency of CD8+ T cells from human peripheral blood lymphocyte samples containing IL-2 after ex vivo stimulation with TVEC, gp100, or vehicle control. * indicates significance by one-way ANOVA with Tukey’s post-hoc test, n=6 patients