{
  "abstract": "Background Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy in the United States. Recurrence rates are high and five-year survival remains low, between 18-47% for patients with stage III disease. 1 Even though most EOCs show T cell infiltration (TILs), and increased TILs are positive prognostic indicators, single agent immunotherapy has not yielded meaningful results, presumably due to the complex immunosuppressive locoregional tumor microenvironment.2 3 The diffuse peritoneal metastasis of late-stage tumors provide a strong rational for locoregional, intraperitoneal (IP) chemotherapy. We propose that multipronged immune modulators that target the tumor microenvironment (TME) could favor TIL activation resulting in improved outcome.Methods This investigator-initiated single-arm phase II efficacy/safety trail ( NCT03734692) was run from 2017 to 2025. Platinum sensitive patients with measurable peritoneal disease were eligible for combination therapy with up to six treatment cycles at 3-week intervals of IP cisplatin, IV Pembrolizumab and IP TLR3 ligand Rintatolimod. The primary outcome was objective response rate (ORR) measured by RECIST criteria at 13 weeks. A secondary biologic endpoint included activation and accumulation of tumor-infiltrating CD3+ CD8+ T cells (TILs). Pre and post-treatment formalin-fixed paraffin-embedded tissue slides were stained using 15 cycles of multiplex imaging from CellScape Precise Spatial Proteomics (Bruker Spatial Biology). Stitched images were analyzed using Spatially Intelligent SpaceIQ Platform (PredXBio).Results Of the 27 patients, 24 (88.9%) were evaluable for response. Twelve patients (44.4%) completed all 6 cycles of treatment. The regimen was well tolerated with no grade 4 or 5 toxicities and the most common toxicities being abdominal pain (67%), anemia (79%), fatigue (100%), hypertension (62%), nausea (83%), anorexia (46%) and vomiting (33%). Three patients experienced immune-mediated reactions; one type 1 diabetes diagnosis, one toxic epidermal necrolysis and one adrenal insufficiency. Using RECIST 1.1 criteria the ORR was 50% with five patients (21%) with a complete response and 7 patients (29%) with a partial response and possible prolongations of survival ( figure 1). Digital spatial profiling revealed a higher fraction of CD3+, CD8+, GZMYB+, cells within the tumor area within responders compared to nonresponders with no significant difference observed in regions outside of the tumor (figure 2).Conclusions Combination locoregional chemoimmunotherapy was well tolerated and demonstrated clinical benefit with a 50% ORR, locoregional T cell activation signals, and several EOC patients with durable treatment responses. Correlative biologic studies suggest treatment response is associated with localized enrichment of cytotoxic and memory T cell populations within the TME.Acknowledgements This trial receives support from both Merck and AIM Immunotech.References Heintz AP, et al. Carcinoma of the ovary. FIGO 26th annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet. 2006;95(Suppl 1):S161–192.Santoiemma PP, Powell Jr. DJ. Tumor infiltrating lymphocytes in ovarian cancer. Cancer Biol Ther. 2015;16(6):807–820.Sato E, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A. 2005;102(51):18538–18543.Abstract 1343 Figure 1Participant progress during trial (Time on treatment, Best Response, Death)Abstract 1343 Figure 2Higher fraction of cells in tumor area in responders and no significant difference outside tumor area: CD8+ GZMB+, CD45RO+, CD3+",
  "authors": [
    {
      "affiliations": [
        "UPMC, Pittsburgh, PA, USA"
      ],
      "name": "Mackenzy Radolec"
    },
    {
      "affiliations": [
        "Medical University of South Carolina, Charleston, SC, USA"
      ],
      "name": "Brian Orr"
    },
    {
      "affiliations": [
        "Magee-Womens Research Institute, Pittsburgh, PA, USA"
      ],
      "name": "Mary Strange"
    },
    {
      "affiliations": [
        "Magee-Womens Research Institute, Pittsburgh, PA, USA"
      ],
      "name": "Lixin Zhang"
    },
    {
      "affiliations": [
        "University of Pittsburgh, Pittsburgh, PA, USA"
      ],
      "name": "Sandra Cascio"
    },
    {
      "affiliations": [
        "PredxBio, Inc., Pittsburgh, PA, USA"
      ],
      "name": "Brian Falkenstein"
    },
    {
      "affiliations": [
        "PredxBio, Inc., Pittsburgh, PA, USA"
      ],
      "name": "A Burak Tosun"
    },
    {
      "affiliations": [
        "PredxBio, Inc., Pittsburgh, PA, USA"
      ],
      "name": "S Chakra Chennubhotla"
    },
    {
      "affiliations": [
        "PredxBio, Inc., Pittsburgh, PA, USA"
      ],
      "name": "Filippo Pullara"
    },
    {
      "affiliations": [
        "University of Pittsburgh, Pittsburgh, PA, USA",
        "National Cancer Institute, National Institutes of Health, Shady Groove, MD, USA"
      ],
      "name": "Anda Vlad"
    },
    {
      "affiliations": [
        "UPMC Magee-Womens Hospital, Pittsburgh, PA, USA"
      ],
      "name": "Robert P Edwards"
    }
  ],
  "title": "1343 A phase II trial of combination locoregional chemoimmunotherapy in recurrent platinum-sensitive ovarian cancer triggers a T lymphotactic response correlating with clinical outcomes",
  "uid": "45e46b0a-c50a-5b76-902a-65f747576444"
}