{
  "abstract": "Background The use of immune checkpoint inhibitors (ICIs) has led to a paradigm change in cancer management. Many patients may have inherent primary resistance to ICIs or develop secondary resistance after initial response. The impact of using novel therapeutic combinations of checkpoint blockade (avelumab) with immune stimulating agonists such as anti-OX40 and/or anti-4-1BB on the tumor microenvironment and modulation of the immune response is an intriguing strategy to evaluate how these agents interact and whether the hypothetical rationale for combinations can be translated into augmentation of anti-tumor immunity in solid tumors.Methods We performed whole exome sequencing (WES), bulk RNAseq, multiplex immunofluorescence (mIF) and chromogenic assay immunohistochemistry (IHC) on tumor tissue and flow cytometry of the peripheral blood to study changes between post and pre-treatment longitudinal changes following the combination of avelumab with utomilumab (a 4-1BB agonist) (arm A), PF-04518600 (an OX40 agonist) (arm B), utomilumab and PF-04518600 (arm C) and utomilumab and radiotherapy (arm D) in phase I/II study ( NCT03217747). Wilcoxon signed rank test was applied.Results We observed low tumor mutation burden (TMB<6) (median: 1.88), alteration of RTK-RAS, TP53, PI3K and WNT pathways across the cohorts. Mutations in TP53, TTN and KRAS (mostly p.G12C, p.G12D) genes and copy number variations (CNV) were found in PIK3CA, CCNE1 and KRAS. Interferon gamma signaling pathway was only enriched early on-treatment after immune stimulating agonists in tumors from patients with colorectal and pancreatic cancers with in arm C. Patients deriving clinical benefit (CR/PR/SD≥4 months) displayed higher T- cell lymphocytes frequencies at baseline (p=0.0157), C1D15 (p=0.0086), and C3D15 (p=0.0070) than patients without clinical benefit in mIF data.Conclusions Our findings, though limited, highlight genomic differences between histologic subsets and outcome as well as the need for combination strategies that drive the recruitment and/or priming of anti-tumor T cells and address low immune permissive tumor states in patients with advanced solid tumors.Trial Registration NCT03217747Acknowledgements The study was financially supported by Pfizer as part of a previous alliance between Pfizer and the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID:10.13039/100009945)Ethics Approval The study was approved by the institutional review board at The University of Texas MD Anderson Cancer Center.",
  "authors": [
    {
      "affiliations": [
        "UT MD Anderson Cancer Center, Pearland, TX, USA",
        "Department of Bioinformatics, The University of Texas MD Anderson Cancer Center Houston, TX, USA"
      ],
      "name": "Nejla Ozirmak Lermi"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Mohamed A Gouda"
    },
    {
      "affiliations": [
        "Developmental Therapeutics Clinic (DTC) Early Phase Clinical Trials Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Jibran Ahmed"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Xianli Jiang"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Younghee Lee"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Vakul Mohanty"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Mohamed H Derbala"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Bettzy Stephen"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Department of Radiation Oncology, Houston, TX, USA"
      ],
      "name": "Anuja Jhingran"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Mohammed M Mohammed"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Donghyun Joo"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Alejandro F Francisco Cruz"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Caddie Laberiano"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Claudio Arrrechedera"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Renganayaki Pandurengan"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Serdar A Gurses"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Yali Yang"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Luisa M Solis Soto"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Jordi Rodon"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Ken Chen"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Funda Meric-Bernstam"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Eugene Koay"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Milind Javle"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Cara L Haymaker"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Aung Naing"
    }
  ],
  "title": "191 Tumor microenvironment changes after treatment with avelumab combinations in patients with advanced solid tumors",
  "uid": "00b55881-61ab-5487-b164-bcb41fb8cbdc"
}