{
  "abstract": "Background Treatment with androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI) is standard of care for newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC). The addition of radiation (RT) to the primary prostate for patients with low-volume disease further improves clinical outcomes. Given the potential for enhanced anti-tumor immune responses with combined immune checkpoint blockade (ICB) and hormonal therapy/RT, we tested the combination of atezolizumab (PD-L1 blockade) plus ARPI, ADT and RT to the prostate in men with mCSPC in the SAABR trial (NCT 04262154). We previously reported clinical outcomes. Here we present deep immune profiling of a unique cohort of paired biopsies and longitudinal blood samples from study patients and characterize both the local and systemic immune response to therapy.Methods Tumor DNA was sequenced using MSK-IMPACT (505-gene NGS panel) on pre-treatment biopsies and matched normal blood. Peripheral immune profiling was performed using Expanded CRISPR-compatible Cellular Indexing of Transcriptomes and Epitopes by sequencing (ECCITE-seq) on 100 PBMC samples collected at distinct timepoints (pre-treatment, post-atezolizumab/pre-SBRT, and post-SBRT). Spatial transcriptomics on pre/post-treatment paired tumor tissue was conducted using the Xenium 5K Pan Tissue and Pathways panel.Results Among 21 patients with baseline tumor sequencing, 48% harbored TP53 or PTEN mutations, and 20% had alterations in homologous recombination repair. ECCITE-seq revealed a significant increase in circulating activated NK cells post-atezolizumab (p<0.05), followed by a decline after SBRT (p<0.05), indicating transient innate immune activation. Xenium spatial transcriptomics successfully profiled paired pre/on-treatment intact tumor tissue with comprehensive assessment of >300,000 individual cells. We demonstrated that while atezolizumab had minimal effects on CD8 T cell abundance or function in prostate cancer, it led to a significant increase in tumor innate lymphoid cells including NK cells/γδ T Cells (p=0.027).Conclusions We present amongst the most comprehensive spatial transcriptomic analyses of prostate cancer conducted to date. A key finding is that atezolizumab increases innate lymphoid cell activation in prostate cancer which could inform the design of future combination immunotherapy approaches for immunologically ‘cold’ tumors like prostate cancer. Furthermore, we identify circulating immune dynamics that provide insights into the optimal timing of therapy and potential biomarkers that require further validation.Trial Registration ClinicalTrials.gov registration: NCT04262154Consent Written informed consent was obtained from the patients for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.Ethics Approval The study was approved by Memorial Sloan Kettering Cancer Center‘s Institutional Review Board. IRB# 19-461 Initial Approval Date:10-Dec-2019 Last IRB Approved: 23-Jul-2024",
  "authors": [
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Matthew Dallos"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Patrick McCann"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Nicolas Andrews"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Kevin M DeRudder"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Kendall Garrett"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Jodi-Ann McDonald"
    },
    {
      "affiliations": [
        "Columbia University Medical Center, New York, NY, USA"
      ],
      "name": "Mark Stein"
    },
    {
      "affiliations": [
        "Columbia University Medical Center, New York, NY, USA"
      ],
      "name": "Israel Deutsch"
    },
    {
      "affiliations": [
        "Columbia University Medical Center, New York, NY, USA"
      ],
      "name": "Catherine Spina"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Celine Nguyen"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Azusa Okada"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Meghan Lloyd"
    },
    {
      "affiliations": [
        "Your PC.Help, Fort Meyers, FL, USA"
      ],
      "name": "Jan Manarite"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Dana Rathkopf"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Sean McBride"
    }
  ],
  "title": "433 Tumor and circulating immune dynamics in prostate cancer treated with PD-L1 blockade, radiation and hormonal therapy: a multiparametric translational analysis from the SAABR trial",
  "uid": "6901d536-3c39-539b-8d92-c06a3ff532c1"
}