{
  "abstract": "Background γδ T cells possess unique immunological features including tissue tropism, major histocompatibility complex-independent antigen recognition, and hybrid T/natural killer cell properties that make them promising candidates for cancer immunotherapy. However, the therapeutic potential of Vδ1 γδ T cells, particularly when engineered with chimeric antigen receptors (CARs), remains underexplored in solid tumors such as pancreatic cancer (PC), largely due to their low abundance in peripheral blood and challenges in ex vivo expansion. This study aims to directly compare the preclinical safety and efficacy among CAR-engineered Vδ1 γδ T cells, Vδ2 γδ T cells, and conventional αβ T cells.Methods We developed a CAR targeting prostate stem cell antigen (PSCA) and engineered it into human blood-derived Vδ1 γδ T cells. These PSCA CAR-Vδ1 T cells were evaluated for antitumor activity against PSCA-expressing pancreatic tumor cells using both in vitro cytotoxicity assays and in vivo xenograft mouse models. Comparative analyses were conducted using PSCA CAR-Vδ1 γδ T cells, PSCA CAR-Vδ2 γδ T cells, and PSCA CAR-αβ T cells. Safety assessments of these CAR-engineered T cell subsets were conducted to evaluate graft-versus-host disease (GvHD) and cytokine release syndrome (CRS), while exhaustion profiles were assessed using single-cell RNA sequencing.Results Our study demonstrated that PSCA CAR-Vδ1 γδ T cells, PSCA CAR-Vδ2 γδ T cells, and PSCA CAR-αβ T cells exhibited similar antitumor efficacy. However, PSCA CAR-Vδ1 T cells did not exhibit GvHD or CRS compared with CAR-αβ T cells. PSCA CAR-Vδ1 T cells also had lower scores for exhaustion when compared with PSCA CAR-Vδ2 T cells by single-cell transcriptomic analysis.Conclusion PSCA CAR-Vδ1 γδ T cells represent a potent and safe therapeutic modality for PSCA + PC, with efficacy comparable to other CAR T cell types and potential advantages in safety and persistence. These findings support further development of CAR-Vδ1 T cell immunotherapy for solid tumors.",
  "authors": [
    {
      "affiliations": [
        "Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California, USA",
        "Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, California, USA"
      ],
      "name": "Zhixin Li"
    },
    {
      "affiliations": [
        "Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California, USA",
        "Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, California, USA"
      ],
      "name": "Ningyuan Liu"
    },
    {
      "affiliations": [
        "Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California, USA",
        "Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, California, USA"
      ],
      "name": "Zahir Shah"
    },
    {
      "affiliations": [
        "Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California, USA",
        "Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, California, USA"
      ],
      "name": "Lewei Jin"
    },
    {
      "affiliations": [
        "Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California, USA",
        "Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, California, USA"
      ],
      "name": "Lei Tian"
    },
    {
      "affiliations": [
        "Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California, USA",
        "Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, California, USA"
      ],
      "name": "Xiaolei Sun"
    },
    {
      "affiliations": [
        "Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, California, USA"
      ],
      "name": "Jianying Zhang"
    },
    {
      "affiliations": [
        "Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California, USA",
        "Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, California, USA"
      ],
      "name": "Zhiyao Li"
    },
    {
      "affiliations": [
        "Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California, USA",
        "Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, California, USA",
        "City of Hope Comprehensive Cancer Center, Los Angeles, California, USA"
      ],
      "name": "Michael A Caligiuri"
    },
    {
      "affiliations": [
        "Division of Hematology & Oncology, Department of Medicine, School of Medicine, University of California, Irvine, California, USA",
        "Institute for Precision Cancer Therapeutics and Immuno-Oncology, Chao Family Comprehensive Cancer Center, University of California, Irvine, California, USA",
        "The Clemons Family Center for Transformative Cancer Research, University of California, Irvine, California, USA"
      ],
      "name": "Jianhua Yu"
    }
  ],
  "title": "Comparative efficacy and safety of PSCA CAR-engineered Vδ1 γδ T cells for immunotherapy of pancreatic cancer",
  "uid": "aa7bc30c-9010-57b8-958b-3308213f373d"
}