{
  "abstract": "Background Dysbiosis of gut microbiome leads to resistance to immunotherapy in various advanced solid tumors. CJRB-101 is a live biotherapeutic product consisting of a novel strain belonging to the species Leuconostoc mesenteroides. To modulate the tumor microenvironment, CJRB-101 was combined with pembrolizumab.Methods Preclinical efficacy and mechanistic studies were performed using humanized non-small cell lung cancer (NSCLC) patient-derived xenograft (PDX) models. This is a multicenter, first-in-human, two-part, phase I, open-label study of CJRB-101 (1×10 11 or 4×1011 colony forming unit (CFU)/day) plus pembrolizumab (200 mg every three weeks (Q3W)) in advanced NSCLC, melanoma, and head and neck squamous cell carcinoma in both immune checkpoint inhibitor (ICI)-naive and ICI-refractory settings. The primary endpoint was to assess the dose-limiting toxicities (DLTs), adverse events, and preliminary activity of the combination treatment. Exploratory endpoints included stool metagenomics analysis and pharmacodynamics parameters.Results In four PDX models, CJRB-101 with pembrolizumab demonstrated enhanced antitumor efficacy, showing a tumor growth inhibition (TGI) of 77.3% in the CJRB-101 monotherapy group and 61.9% in the combination group, which was significantly improved compared with pembrolizumab alone. A distinct M2-to-M1 repolarization was observed and validated in vitro. Notably, increased activation of cytotoxic T cells was observed, suggesting an immune-mediated antitumor mechanism of CJRB-101. A total of 42 patients were enrolled in the low-dose cohort (one capsule once a day; n=6) and high-dose cohort (two capsules two times a day, n=36). Metastatic NSCLC accounted for 86% (n=36) and 67% (n=28) of the patients were refractory to ICIs. None of the patients experienced DLT. In ICI-naïve NSCLC (n=12) with programmed death-ligand 1 (PD-L1) >50%, the overall response rate (ORR) and disease control rate (DCR) were 58% and 75%, respectively. The ORR was 5% and DCR was 41% in the ICI-refractory NSCLC (n=22) with an ORR of 5% and DCR of 41%. After a median follow-up of 15.6 months and 8.9 months for ICI-naïve and ICI-refractory NSCLC, the median progression-free survival was 9 months (95% CI 5.6 to not reached) and 1.8 months (95% CI 1.6 to 4.3), respectively. CJRB-101 plus pembrolizumab was well-tolerated, and none of the patients experienced grade >3 treatment-related adverse events.Conclusions Early clinical data show encouraging antitumor response of CJRB-101 plus pembrolizumab in ICI-naïve metastatic NSCLC with PD-L1 >50%.Trial registration number NCT05877430.",
  "authors": [
    {
      "affiliations": [
        "Department of Internal Medicine and Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea (the Republic of)"
      ],
      "name": "Jii Bum Lee"
    },
    {
      "affiliations": [
        "Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea (the Republic of)"
      ],
      "name": "Sujeong Baek"
    },
    {
      "affiliations": [
        "Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea (the Republic of)"
      ],
      "name": "Dong Kwon Kim"
    },
    {
      "affiliations": [
        "CJ Bioscience, Inc, Seoul, Korea (the Republic of)"
      ],
      "name": "Bo-Eun Kwon"
    },
    {
      "affiliations": [
        "Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Jongno-gu, Seoul, Korea (the Republic of)"
      ],
      "name": "Jin Seok Ahn"
    },
    {
      "affiliations": [
        "Division of Hematology-Oncology, University of California Irvine School of Medicine, Irvine, California, USA"
      ],
      "name": "Misako Nagasaka"
    },
    {
      "affiliations": [
        "Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"
      ],
      "name": "Diwakar Davar"
    },
    {
      "affiliations": [
        "CJ Bioscience, Inc, Seoul, Korea (the Republic of)"
      ],
      "name": "Hyunkyung Park"
    },
    {
      "affiliations": [
        "CJ Bioscience, Inc, Seoul, Korea (the Republic of)"
      ],
      "name": "Hyunjeong Kim"
    },
    {
      "affiliations": [
        "CJ Bioscience, Inc, Seoul, Korea (the Republic of)"
      ],
      "name": "Jieun Im"
    },
    {
      "affiliations": [
        "CJ Bioscience, Inc, Seoul, Korea (the Republic of)"
      ],
      "name": "Junwon Yang"
    },
    {
      "affiliations": [
        "CJ Bioscience, Inc, Seoul, Korea (the Republic of)"
      ],
      "name": "Eunchong Yang"
    },
    {
      "affiliations": [
        "CJ Bioscience, Inc, Seoul, Korea (the Republic of)"
      ],
      "name": "Ga-Hyun Shin"
    },
    {
      "affiliations": [
        "CJ Bioscience, Inc, Seoul, Korea (the Republic of)"
      ],
      "name": "Soeun Choi"
    },
    {
      "affiliations": [
        "CJ Bioscience, Inc, Seoul, Korea (the Republic of)"
      ],
      "name": "Ji-Eun Kwon"
    },
    {
      "affiliations": [
        "CJ Bioscience, Inc, Seoul, Korea (the Republic of)"
      ],
      "name": "Jae-Min Kim"
    },
    {
      "affiliations": [
        "CJ Bioscience, Inc, Seoul, Korea (the Republic of)"
      ],
      "name": "So-Yeong Kang"
    },
    {
      "affiliations": [
        "Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea (the Republic of)"
      ],
      "name": "Youngtaek Kim"
    },
    {
      "affiliations": [
        "Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea (the Republic of)"
      ],
      "name": "So Young Park"
    },
    {
      "affiliations": [
        "Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea (the Republic of)",
        "Yonsei New Il Han Institute for Integrative Lung Cancer Research, Yonsei University College of Medicine, Seoul, Korea (the Republic of)"
      ],
      "name": "Jae Hwan Kim"
    },
    {
      "affiliations": [
        "CJ Bioscience, Inc, Seoul, Korea (the Republic of)"
      ],
      "name": "Hyun-Seok Oh"
    },
    {
      "affiliations": [
        "CJ Bioscience, Inc, Seoul, Korea (the Republic of)"
      ],
      "name": "Mauricio Chalita"
    },
    {
      "affiliations": [
        "CJ Bioscience, Inc, Seoul, Korea (the Republic of)"
      ],
      "name": "Arim Min"
    },
    {
      "affiliations": [
        "Department of Internal Medicine and Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea (the Republic of)",
        "Yonsei New Il Han Institute for Integrative Lung Cancer Research, Yonsei University College of Medicine, Seoul, Korea (the Republic of)"
      ],
      "name": "Byoung Chul Cho"
    }
  ],
  "title": "Phase I trial of CJRB-101 plus pembrolizumab in patients with metastatic non-small cell lung cancer, head and neck squamous cell carcinoma and melanoma",
  "uid": "c8e84f2e-47d5-5451-a3bd-49f33f30b7f6"
}