{
  "abstract": "Background GEN2 is a non-replicating gene transfer vector encoding for an enhanced viral thymidine kinase (HSV-eTK) and the cytokine GM-CSF. When transduced into a tumor cell and in the presence of valganciclovir (VGCV), HSV-eTK triggers cancer cell death by DNA chain termination and release of unique tumor antigens including neoantigens (NA). Local secretion of hGM-CSF augments an immunotherapeutic effect by enhancing NA presentation to local immune effector cells. GEN2 is administered by intravenous (IV) dosing.Methods This is an open label, Phase 1 study in adult patients with advanced solid tumors to determine the recommended Phase 2 dose for GEN2 by IV infusion (given on Days 1, 3 and 8 q4w) followed by VGCV on Days 12-21 every cycle. Secondary objectives: immunogenicity, PK and preliminary anti-tumor activity. Exploratory endpoints include assessment of vector persistence in peripheral blood mononuclear cells (PBMCs), changes in cytokines, circulating immune cells, and tissue changes in paired biopsies. Dose escalation for the first 4 dose levels occurred in semi-log increments, followed by dose doubling.Results As of 20 June 2025, 15 patients have been treated at 5 Dose Levels (DLs between 3.4E+6 and 2E +8 TU/kg). Treatment duration ranges from 1 to 11+ weeks. Median age 67; 7 females; common tumor types: colorectal cancer (n=4) and cholangiocarcinoma (n=2). Patients had a median of 3 prior lines of therapy (range 3-5). Treatment related adverse events (TRAEs) were all grade 1-2: diarrhea (n = 4), nausea (n = 2), vomiting (n = 3), dizziness, headache, chills, fatigue, neck pain and hyperhidrosis (1 patient each). Dose Limiting Toxicity has not been observed. No patient discontinued treatment due to a related AE. PK data: elimination half-life 0.4 hours; Cycle 1 Day 1 Cmax and AUC0-t increased linearly over the dose range. Consistent pharmacodynamic changes (both vector persistence in PBMC DNA and quantitation of GM-CSF in plasma) were observed starting at DL4. DL5 was declared a Maximally Administered Dose. DL4 (n=5): stable disease (n=2); DL5 (n=6): 1 SD with 3 patients active in Cycle 1-2. Analysis of additional correlative data including immune biomarkers is in progress (to be presented at the meeting).Conclusions GEN2 is well tolerated without DLTs. Three dose expansion cohorts (hepatocellular (HCC), HR+ breast and cutaneous malignancies) are open for enrollment. A parallel cohort for intratumoral injection continues in cutaneous malignancies. Additional cohorts combining GEN2 with a checkpoint inhibitor will occur in melanoma and HCC ( NCT06391918).Trial Registration NCT06391918Ethics Approval The study obtained ethics approval from the following institutional review boards: USC IRB, #HS-24-00114; COH WCG IRB, #20240061; and SALUS IRB, #GVO-1102_NXVIT23.74. Participants gave informed consent before taking part in this study.",
  "authors": [
    {
      "affiliations": [
        "University of Southern California, Los Angeles, CA, USA",
        "USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA"
      ],
      "name": "Anthony El-Khoueiry"
    },
    {
      "affiliations": [
        "NEXT Oncology, Virginia Cancer Specialists, Fairfax, VA, USA"
      ],
      "name": "Alexander I Spira"
    },
    {
      "affiliations": [
        "USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA"
      ],
      "name": "Diana L Hanna"
    },
    {
      "affiliations": [
        "University of Southern California, Keck School of Medicine, Los Angeles, CA, USA"
      ],
      "name": "Jacob S Thomas"
    },
    {
      "affiliations": [
        "City of Hope, Duarte, CA, USA"
      ],
      "name": "Gagandeep Brar"
    },
    {
      "affiliations": [
        "NEXT Oncology, Fairfax, VA, USA"
      ],
      "name": "Neel Belani"
    },
    {
      "affiliations": [
        "Sarah Cannon Research Institute, Nashville, TN, USA"
      ],
      "name": "Meredith Mckean"
    },
    {
      "affiliations": [
        "Indiana University School of Medicine, Indianapolis, IN, USA"
      ],
      "name": "Kathy Miller"
    },
    {
      "affiliations": [
        "GenVivo, San Marino, CA, USA"
      ],
      "name": "Tara Quang"
    },
    {
      "affiliations": [
        "GenVivo, San Marino, CA, USA"
      ],
      "name": "Allen Wang"
    },
    {
      "affiliations": [
        "GenVivo, San Marino, CA, USA"
      ],
      "name": "Sonia Macia"
    },
    {
      "affiliations": [
        "GenVivo, San Marino, CA, USA"
      ],
      "name": "Hirdesh Uppal"
    },
    {
      "affiliations": [
        "GenVivo, San Marino, CA, USA"
      ],
      "name": "Robert G Johnson"
    },
    {
      "affiliations": [
        "GenVivo, San Marino, CA, USA"
      ],
      "name": "Alison L Hannah"
    },
    {
      "affiliations": [
        "City of Hope, Duarte, CA, USA"
      ],
      "name": "Daneng Li"
    }
  ],
  "title": "573 Phase 1 study of GEN2, a personalizing systemic cancer immunotherapy, in adult patients with advanced solid tumor malignancies",
  "uid": "46b23894-111f-5b77-93d3-b3fbc559dcbc"
}