{
  "abstract": "Background Prostate cancer, a leading cause of cancer-related death in men, is refractory to checkpoint inhibition. 1–3 Lutetium-177-labeled PSMA-617 (177Lu-PSMA, Pluvicto) is an FDA-approved radioligand therapy (RLT) in CRPC. We have shown that a single dose of 177Lu-PSMA is immunomodulatory, and can be safely combined with PD-1 blockade, pembrolizumab, in a phase 1 clinical trial (NCT03805594).4 However, the schedule by which these treatments should be combined is unknown.Methods In our phase 1 clinical trial, patients with mCRPC received a single dose of 177Lu-PSMA either before (Schedule 1, n=30), concurrently with (Schedule 2, n=6), or after pembrolizumab (Schedule 3, n=6). Serial peripheral blood mononuclear cells (PBMCs) were collected and analyzed using multi-omic single-cell RNA sequencing (scRNA-seq) to dissect the immune responses with these 3 schedules.Results We found that a single dose of 177Lu-PSMA in monotherapy led to an expansion of CD4+ effector T cells as well as in Tregs indicative of direct immunomodulatory activity. This was accompanied by a reduction in NK and B cells. When 177Lu-PSMA was combined with pembrolizumab, we saw dynamic changes in non-Treg T cell subsets (CD4+ and CD8+ T cells), dendritic cells (DCs), NK cells, and B cells across all three dosing schedules. Schedules 1 (177Lu-PSMA before) and 2 (concurrent) demonstrated stable T cell levels accompanied by a gradual increase in DCs, whereas Schedule 3 (Pembrolizumab before) was characterized by low T cell frequencies and a progressive decline in DCs relative to baseline.Conclusions Our study demonstrates the critical importance of treatment sequencing to fully harness the immunomodulatory potential of RLT using a single dose of 177Lu-PSMA and optimize synergy with PD-1 blockade in mCRPC. While initiating with either 177Lu-PSMA or concurrently starting 177Lu-PSMA with pembrolizumab resulted in an increase in DCs, initiating pembrolizumab prior to 177Lu-PSMA resulted in lower frequencies of T cells and DCs, which could be detrimental to induction of immune responses.References Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJM, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014 Jun;15(7):700–12.Theelen WSME, Peulen HMU, Lalezari F, van der Noort V, de Vries JF, Aerts JGJV, et al. Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With Advanced Non-Small Cell Lung Cancer: Results of the PEMBRO-RT Phase 2 Randomized Clinical Trial. JAMA Oncology 2019 Sep 1;5(9):1276–82.McBride S, Sherman E, Tsai CJ, Baxi S, Aghalar J, Eng J, et al. Randomized Phase II Trial of Nivolumab With Stereotactic Body Radiotherapy Versus Nivolumab Alone in Metastatic Head and Neck Squamous Cell Carcinoma. J Clin Oncol. 2021 Jan 1;39(1):30–7.Aggarwal R, Starzinski S, Kouchkovsky I de, Koshkin V, Bose R, Chou J, et al. Single-dose 177Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: an open-label, dose-expansion, phase 1 trial. The Lancet Oncology 2023 Nov 1;24(11):1266–76.",
  "authors": [
    {
      "affiliations": [
        "Fred Hutchinson Cancer Center, Seattle, WA, USA"
      ],
      "name": "Anusha Muralidhar"
    },
    {
      "affiliations": [
        "Fred Hutchinson Cancer Center, Seattle, WA, USA"
      ],
      "name": "Karen Law"
    },
    {
      "affiliations": [
        "University of California San Francisco, San Francisco, CA, USA"
      ],
      "name": "Zenghua Fan"
    },
    {
      "affiliations": [
        "Fred Hutchinson Cancer Center, Seattle, WA, USA"
      ],
      "name": "Shloka Shukla"
    },
    {
      "affiliations": [
        "Fred Hutchinson Cancer Center, Seattle, WA, USA"
      ],
      "name": "Aram Lyu"
    },
    {
      "affiliations": [
        "University of California San Francisco, San Francisco, CA, USA"
      ],
      "name": "Matthew Clark"
    },
    {
      "affiliations": [
        "University of California San Francisco, San Francisco, CA, USA"
      ],
      "name": "Averey Lea"
    },
    {
      "affiliations": [
        "University of California San Francisco, San Francisco, CA, USA"
      ],
      "name": "Serena S Kwek"
    },
    {
      "affiliations": [
        "University of California San Francisco, San Francisco, CA, USA"
      ],
      "name": "Michael Evans"
    },
    {
      "affiliations": [
        "University of California San Francisco, San Francisco, CA, USA"
      ],
      "name": "Rahul R Aggarwal"
    },
    {
      "affiliations": [
        "Fred Hutchinson Cancer Center, Seattle, WA, USA"
      ],
      "name": "Lawrence Fong"
    }
  ],
  "title": "674 Multi-omic single-cell assessment of castration-resistant prostate cancer patients receiving ¹7\n7Lu-PSMA-617 and pembrolizumab shows timing of radioligand therapy alters immune response",
  "uid": "16395dc7-dadd-5ba2-9b03-9bfb519a472a"
}