{
  "abstract": "Background RP1 (vusolimogene oderparepvec) is a herpes simplex virus type 1 (HSV-1)-based oncolytic immunotherapy expressing GM-CSF and GALV-GP-R −.1 The IGNYTE trial (data cutoff: 08MAR2024) showed an objective response rate (ORR) of 32.9% (15.0% complete response [CR]) in patients with anti-PD-1-failed melanoma treated with RP1 + nivolumab by blinded independent central review [BICR] using RECIST 1.1; median duration of response (DOR) was 33.7 months.2 Here we present pharmacodynamic data from paired tumor biopsies and blood samples supporting a follow-up efficacy analysis with a data cutoff of 15OCT2024.Methods Patients with advanced melanoma and confirmed disease progression during ≥8 weeks of anti-PD-1±CTLA-4 as the last prior treatment were enrolled (N=140; NCT03767348).2 For biomarker analysis, tumor biopsies were taken from the same lesion pretreatment and 43 days after the first RP1 dose. The tumor microenvironment was analyzed by immunohistochemistry (CD8 [n=46], PD-L1 [n=45]) and multiplex immunofluorescence. RNA sequencing (NovaSeq 6000) was performed on pre- and post-treatment biopsies from 19 patients, with same lesion biopsies available from 9 non-responders and 10 responders. Correlation analyses assessed baseline vs on-treatment gene expression and baseline tumor mutation burden (TMB) by clinical response. The CDR3 regions of TCRβ chains were sequenced from peripheral blood mononuclear cell DNA using the ImmunoSEQ assay.Results By the data cutoff, 1 additional response had been documented as compared to the primary analysis, giving an ORR of 33.6% (16.4% CR) and median DOR (95% confidence interval) of 24.8 (14.1-not reached) months. Increased CD8 and PD-L1 expression were observed in paired biopsies from 17/46 (37%) and 25/45 (56%) patients, respectively. RNA sequencing demonstrated increased T-cell functionality, with upregulation of genes linked to activation, cytotoxicity ( GZMA, TNF, IFNG, PRF1), IFNγ signaling, and antigen presentation, confirming conversion to a more immunologically active tumor microenvironment. Increased PD-L1+CD68+ macrophages and PD-1+CD8+ T cells were also observed. Systemic anti-tumor immunity was evidenced by the expansion of tumor- and HSV-1-specific T cells in blood. These pharmacodynamic changes occurred predominantly in responders, including patients with no response to prolonged use of prior ipilimumab/nivolumab. No correlation was seen between TMB and clinical response.Conclusions Biomarker data demonstrated increased expression of a range of genes known to be associated with responsiveness to anti-PD-1 therapy, which is consistent with and provides a mechanistic basis for the observed clinical responses to RP1 + nivolumab after prior anti-PD-1 failure ( figure 1).Trial Registration NCT03767348References Thomas S, Kuncheria L, Roulstone V, et al. Development of a new fusion-enhanced oncolytic immunotherapy platform based on herpes simplex virus type 1. J Immunother Cancer. 2019;7:214.Wong MK, Milhem MM, Sacco JJ, et al. RP1 combined with nivolumab in advanced anti-PD-1-failed melanoma (IGNYTE). J Clin Oncol. 2025;10.1200/JCO-25-01346.Ethics Approval The study was conducted in accordance with the ethical principles originating from the Declaration of Helsinki and was approved by the institutional review board/ethics committee at each participating site. Written informed consent was obtained from all patients prior to the conduct of any study-related procedures.Abstract 1327 Figure 1Pharmacodynamic changes observed with RP1 plus nivolumab treatment following progression on anti-PD-1 therapy. Patients enrolled in the IGNYTE study experienced progression on anti-PD-1 therapy, making the observed pharmacodynamic changes (reversal of T-cell infiltration, increase in PD-L1 expression, increase in IFNγ signature, and increase in antigen presentation machinery) in tumors a likely contributor to RP1’s mechanism of action.aPrevious line anti-PD-1-based therapies can include treatments such as ipilimumab, nivolumab, or pembrolizumab in combination with immunotherapies targeting proteins such as CTLA-4 or LAG-3.bDrawings of melanoma and sites of metastases are for illustrative purposes only and are meant to show extent of potential disease progression.cAssessed by blinded independent central review.dEstimated using the reverse Kaplan-Meier method.1L, first line; 2L, second line; CI, confidence interval; CR, complete response; CTLA-4, cytotoxic T-lymphocyte associated protein 4; DOR, duration of response; HLA-DRA, major histocompatibility complex, class II, DR alpha; HLA-E, major histocompatibility complex, class I, alpha chain E; IFNγ, interferon gamma; LAG-3, lymphocyte-activation gene 3; MHC, major histocompatibility complex; NR, not reached; ORR, overall response rate; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PR, partial response; RECIST 1.1, Response Evaluation Criteria in Solid Tumors version 1.1.",
  "authors": [
    {
      "affiliations": [
        "University of Cincinnati Cancer Center, University of Cincinnati, Cincinnati, OH, USA"
      ],
      "name": "Trisha M Wise-Draper"
    },
    {
      "affiliations": [
        "Replimune Inc., Woburn, MA, USA"
      ],
      "name": "Praveen K Bommareddy"
    },
    {
      "affiliations": [
        "Gustave Roussy and Paris-Saclay University, Villejuif, France"
      ],
      "name": "Caroline Robert"
    },
    {
      "affiliations": [
        "University of Liverpool, Liverpool, UK",
        "The Clatterbridge Cancer Centre, Wirral, UK"
      ],
      "name": "Joseph J Sacco"
    },
    {
      "affiliations": [
        "University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA, USA"
      ],
      "name": "Gino K In"
    },
    {
      "affiliations": [
        "Vall d’Hebron Institute of Oncology (VHIO) and Vall d’Hebron Hospital Medical Oncology Department, Barcelona, Spain"
      ],
      "name": "Eva Muñoz Couselo"
    },
    {
      "affiliations": [
        "National Center for Tumor Diseases (NCT-West), Campus Essen and University Alliance Ruhr, Research Alliance Ruhr, Research Center One Health, University Duisburg-Essen, Campus Essen, Essen, Germany",
        "Department of Dermatology, West German Cancer Center, University Hospital Essen, Essen, Germany"
      ],
      "name": "Dirk Schadendorf"
    },
    {
      "affiliations": [
        "Banner MD Anderson Cancer Center, Gilbert, AZ, USA"
      ],
      "name": "Jiaxin Niu"
    },
    {
      "affiliations": [
        "Duke Cancer Institute, Duke University, Durham, NC, USA"
      ],
      "name": "Georgia M Beasley"
    },
    {
      "affiliations": [
        "Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA"
      ],
      "name": "Bartosz Chmielowski"
    },
    {
      "affiliations": [
        "Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA"
      ],
      "name": "Mohammed M Milhem"
    },
    {
      "affiliations": [
        "Intermountain Medical Center, Murray, UT, USA"
      ],
      "name": "Tawnya Lynn Bowles"
    },
    {
      "affiliations": [
        "Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA"
      ],
      "name": "Katy K Tsai"
    },
    {
      "affiliations": [
        "Université Paris Cité, APHP Dermato-Oncology and CIC, Cancer Institute AP-HP. Nord-Université Paris Cité, INSERM U976, Saint Louis Hospital, Paris, France"
      ],
      "name": "Céleste Lebbé"
    },
    {
      "affiliations": [
        "Aix-Marseille Université, APHM, Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM, U1068, CNRS, UMR7258, UM105, Hôpital Timone, CEPCM, Dermatology and Skin Cancer Department, Marseille, France"
      ],
      "name": "Caroline Gaudy-Marqueste"
    },
    {
      "affiliations": [
        "Leeds Institute of Medical Research at St. James’s, University of Leeds, Leeds, UK"
      ],
      "name": "Adel Samson"
    },
    {
      "affiliations": [
        "Replimune Inc., Woburn, MA, USA"
      ],
      "name": "Junhong Zhu"
    },
    {
      "affiliations": [
        "Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA"
      ],
      "name": "Marcus Viana"
    },
    {
      "affiliations": [
        "Replimune Inc., Woburn, MA, USA"
      ],
      "name": "Chris Tucci"
    },
    {
      "affiliations": [
        "Replimune Inc., Woburn, MA, USA"
      ],
      "name": "Bhavna Paratala"
    },
    {
      "affiliations": [
        "Replimune Inc., Woburn, MA, USA"
      ],
      "name": "Jeannie W Hou"
    },
    {
      "affiliations": [
        "Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA"
      ],
      "name": "Michael K Wong"
    }
  ],
  "title": "1327 Biomarker and updated clinical data for RP1 plus nivolumab in anti-PD-1-failed melanoma from the IGNYTE trial demonstrate reversal of mechanisms of resistance to immune checkpoint blockade",
  "uid": "d35125dd-01ee-5490-a61e-da6b044d7608"
}