{
  "abstract": "Background The aggressive nature and dismal prognosis of glioblastoma may partly be due to its limited ability to induce anti-tumor T cell responses within the brain. Using vaccines to generate tumor-specific T cells may be beneficial to patients if the T cells can traffic to the brain and maintain functionality within the immunosuppressive tumor microenvironment. Heterologous prime-boost vaccination with chimpanzee adenovirus (ChAdOx1) and modified vaccinia Ankara (MVA) viral vectors can generate high frequencies of CD8 + T cells specific for tumor antigens,1 but this has not been studied in glioblastoma. Therefore, we used preclinical models to determine whether this vaccination strategy could induce effective T cell responses in the brain.Methods We tested this vaccination strategy against the poorly immunogenic, syngeneic, orthoptic SB28 glioblastoma model. As endogenous SB28 antigens were unknown, we created a transgenic SB28.P1A model expressing P1A, a murine tumor-associated antigen (TAA), which we targeted with ChAdOx1/MVA-P1A vaccines. Furthermore, we developed a pipeline to identify novel SB28 TAAs, which we screened for off-target expression, immunogenicity, and therapeutic targetability by creating TAA-encoding ChAdOx1/MVA vaccines.Results Prophylactic ChAdOx1/MVA vaccination significantly prolonged the survival of mice challenged with tumors compared to controls in the context of P1A and a novel TAA (n=15-20/group, p=0.0034, p<0.0001), with 30% and 50% showing complete remission, respectively. A significant survival benefit was also observed in the therapeutic setting, with vaccination starting 7 days post-tumor implantation, following confirmation of tumor establishment (n=15-20/group, P1A: p=0.0047, TAA: p=0.0119). The tumor-bearing brains of vaccinated mice were enriched for antigen-specific CD8+ T cells (25% of CD8 + T cells vs. 5% in blood), of which 50% had a CD103+CD69+T resident memory-like (TRM) phenotype. Long-term surviving mice maintained consistent levels of antigen-specific TRM in their brains 70 and 175 days post-tumor challenge, despite a three-fold decrease in circulating antigen-specific T cells, indicating parenchymal TRM durability. Furthermore, survivors were protected against orthotopic but not subcutaneous rechallenge, demonstrating tissue-specific memory. Adoptive transfer of P1A-specific TRM cells derived from vaccinated tumor-bearing mice into the brains of naïve mice protected mice from later tumor challenge (n=10/group, p=0.0233), while P1A-specific non-TRM cells or non-P1A-specific brain-derived CD8+ T cells did not, demonstrating that antigen-specific TRMs are sufficient to mediate anti-glioblastoma immunity.Conclusions ChAdOx1/MVA vaccination induced high frequencies of antigen-specific TRMs with functional memory and long-term durability in the brain. These TRMs were sufficient to protect against glioblastoma, making this vaccination strategy an attractive candidate for translation into clinical trials.Reference McAuliffe J, Chan HF, Noblecourt L, Ramirez-Valdez RA, Pereira-Almeida V, Zhou Y, Pollock E, Cappuccini F, Redchenko I, Hill AV, Leung CSK, Van den Eynde BJ. Heterologous prime-boost vaccination targeting MAGE-type antigens promotes tumor T-cell infiltration and improves checkpoint blockade therapy. J Immunother Cancer. 2021 Sep;9(9):e003218Ethics Approval All animal work was approved by either the University of Oxford Animal Care and Ethical Review Committee and experimental procedures were carried out in accordance with the terms of the UK Animals (Scientific Procedures) Act Project Licenses P0D369534 and PB050649E; or by the National Cancer Institute-Bethesda Animal Care and Use Committee and experimental procedures were carried out in accordance with the terms of Protocol NOB-024.",
  "authors": [
    {
      "affiliations": [
        "National Cancer Institute, Bethesda, MD, USA",
        "University of Oxford, Oxford, Oxfordshire, UK"
      ],
      "name": "Emily E Steffke"
    },
    {
      "affiliations": [
        "National Cancer Institute, Bethesda, MD, USA"
      ],
      "name": "Laila Latifi"
    },
    {
      "affiliations": [
        "National Cancer Institute, Bethesda, MD, USA"
      ],
      "name": "Morgan J Coombs"
    },
    {
      "affiliations": [
        "National Cancer Institute, Bethesda, MD, USA"
      ],
      "name": "Ayaka Hara"
    },
    {
      "affiliations": [
        "National Cancer Institute, Bethesda, MD, USA"
      ],
      "name": "Jo Spurgeon"
    },
    {
      "affiliations": [
        "National Cancer Institute, Bethesda, MD, USA"
      ],
      "name": "Brita Anderson"
    },
    {
      "affiliations": [
        "National Cancer Institute, Bethesda, MD, USA"
      ],
      "name": "John C Hancock"
    },
    {
      "affiliations": [
        "National Cancer Institute, Bethesda, MD, USA"
      ],
      "name": "Caitlin Huguely"
    },
    {
      "affiliations": [
        "University of Oxford, Oxford, Oxfordshire, UK"
      ],
      "name": "Vinnycius Pereira Almeida"
    },
    {
      "affiliations": [
        "University of Oxford, Oxford, Oxfordshire, UK"
      ],
      "name": "James AS McAuliffe"
    },
    {
      "affiliations": [
        "University of Oxford, Oxford, Oxfordshire, UK"
      ],
      "name": "Amanda Wicki"
    },
    {
      "affiliations": [
        "University of Oxford, Oxford, Oxfordshire, UK"
      ],
      "name": "Laurine Noblecourt"
    },
    {
      "affiliations": [
        "National Cancer Institute, Bethesda, MD, USA"
      ],
      "name": "Wei Zhang"
    },
    {
      "affiliations": [
        "National Cancer Institute, Bethesda, MD, USA"
      ],
      "name": "Meili Zhang"
    },
    {
      "affiliations": [
        "National Cancer Institute, Bethesda, MD, USA"
      ],
      "name": "Dionne Davis"
    },
    {
      "affiliations": [
        "National Cancer Institute, Bethesda, MD, USA"
      ],
      "name": "Nicole Briceno"
    },
    {
      "affiliations": [
        "National Cancer Institute, Bethesda, MD, USA"
      ],
      "name": "Hua Song"
    },
    {
      "affiliations": [
        "University of California, San Francisco, San Francisco, CA, USA"
      ],
      "name": "Hideho Okada"
    },
    {
      "affiliations": [
        "National Cancer Institute, Bethesda, MD, USA"
      ],
      "name": "Mark Gilbert"
    },
    {
      "affiliations": [
        "University of Oxford, Oxford, Oxfordshire, UK"
      ],
      "name": "Carol SK Leung"
    },
    {
      "affiliations": [
        "Ludwig Institute for Cancer Research, de Duve Institute, Brussels, Belgium"
      ],
      "name": "Benoit JVan den Eynde"
    },
    {
      "affiliations": [
        "National Cancer Institute, Bethesda, MD, USA"
      ],
      "name": "Masaki Terabe"
    }
  ],
  "title": "1200 Tumor-specific resident memory-like T cells induced by viral vector vaccination mediate protection against orthotopic murine glioblastoma",
  "uid": "18e8f569-5781-5923-8d1f-254f47272d61"
}