{
  "abstract": "Background We previously reported on the clinical activity of an HPV16 cancer vaccine (PDS0101), a tumor-targeting IL-12 immunocytokine (NHS-IL12, PDS01ADC), and a bifunctional agent targeting PD-L1 and TGF-β (bintrafusp alfa, BA) for the treatment of advanced HPV-associated malignancies, which demonstrated promising clinical activity ( NCT04287868).1 Here, we perform a comprehensive survey of the peripheral immunome from patients treated with this novel immunotherapeutic combination to query systemic immunological changes and build models predicting clinical response.Methods Peripheral blood was serially collected from patients (n=50) for HPV16 circulating tumor DNA (ctDNA) detection, qualitative serum proteome profiling with the Olink ImmunoOncology platform, and immunophenotyping by flow cytometry. Patients deriving clinical benefit (CB; complete response, partial response, or stable disease (SD) ≥6 months) were compared to those with no clinical benefit (NCB; progressive disease or SD <6 months). Recursive feature selection was used to identify serum analytes at baseline and changes after 2 weeks that predicted CB in regression models. 2 Results In analyses of patients with HPV16+ disease, lower pre-treatment levels of several soluble immune checkpoints, chemokines, and angiogenic factors associated with CB. Combination therapy induced broad modulation of the immune system with enrichment of serum analytes involved in leukocyte migration, cell killing, and cellular responses to IFNγ pathways. Greater early increases in several granzymes, chemokines, and soluble NK ligands associated with CB. A 3-feature model of serum analytes identified lower baseline interleukin-6 and heme oxygenase-1 and greater early increases in granzyme B as effectively predicting CB (accuracy=0.78; p=4.9x10 -6). This model was also recapitulated with Cox modeling, confirming the validity of these analytes in predicting clinical response. HPV16 ctDNA was detected in 32/36 (89%) evaluable patients with known HPV16+ disease, with lower ctDNA loads, both at baseline and 6 weeks, associated with CB. Inclusion of ctDNA; however, did not improve the serum model predictions. Patients developing CB also had lower frequencies of peripheral monocytes and myeloid derived suppressor cells, and a lower neutrophil to lymphocyte ratio throughout treatment vs patients with NCB, suggestive of systemic immunosuppression in patients with NCB.Conclusions Machine-learning models using serum proteomic data effectively predict patients who derive clinical benefit from treatment with PDS0101, NHS-IL12, and BA, based on baseline levels and early changes in serum analytes. These data pave the way for outcome prediction in patients with HPV-associated malignancies using readily quantifiable molecular correlates from peripheral blood and warrant prospective validation in future clinical studies.Ethics Approval All subjects gave written informed consent. Study protocol ( NCT04287868) was approved by the NIH’s IRB, and conducted in accordance with institutional and federal guidelines.References Floudas CS, Goswami M, Donahue RN, Pastor DM, Redman JM, Brownell I, Turkbey EB, Cordes LM, Steinberg SM, Manu M, Francis DC, Lamping E, Marte JL, Kackley M, Krauss E, Manukyan M, Jochems C, Schlom J, Gulley JL, Strauss J. Novel combination immunotherapy and clinical activity in patients with HPV-associated cancers: a nonrandomized clinical trial. JAMA Oncol. 2025;11:394–399.Toney NJ, Lynch MT, Lynce F, Mainor C, Isaacs C, Schlom J, Donahue RN. Serum analytes as predictors of disease recurrence and the duration of invasive disease-free survival in patients with triple negative breast cancer enrolled in the OXEL trial treated with immunotherapy, chemotherapy, or chemoimmunotherapy. J Immunother Cancer 2025;13:e011379.",
  "authors": [
    {
      "affiliations": [
        "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Megan T Lynch"
    },
    {
      "affiliations": [
        "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Meghali Goswami"
    },
    {
      "affiliations": [
        "National Cancer Institute, Bethesda, MD, USA"
      ],
      "name": "Charalampos S Floudas"
    },
    {
      "affiliations": [
        "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Julius Strauss"
    },
    {
      "affiliations": [
        "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Yo-Ting Tsai"
    },
    {
      "affiliations": [
        "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Jennifer L Marte"
    },
    {
      "affiliations": [
        "National Cancer Institute, Bethesda, MD, USA"
      ],
      "name": "James L Gulley"
    },
    {
      "affiliations": [
        "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Jeffrey Schlom"
    },
    {
      "affiliations": [
        "National Cancer Institute, Center for Immuno-Oncology, Bethesda, MD, USA"
      ],
      "name": "Renee N Donahue"
    }
  ],
  "title": "37 Early changes in serum proteomic profiles predict anti-tumor activity in patients with advanced HPV-associated malignancies treated with novel combination immunotherapy",
  "uid": "faba79d8-ff08-5c4e-9802-64cd801c51ea"
}