{
  "abstract": "Background Extensive-stage solid cancers are often refractory to existing therapies, including Chimeric Antigen Receptor (CAR) T cell therapy. While CAR T cells have revolutionized the treatment of hematologic malignancies, their efficacy in solid cancer is restricted by poor infiltration, hostile tumor microenvironments (TME), and limited persistence. 1 Escalating CAR T cell doses in patients with high-burden solid tumors has not yielded clinical responses,2 while on-target off-tumor toxicity limits dose escalation.3 Few studies have explored how manipulating the TME can address the challenges faced when targeting CAR T cells to advanced solid cancer.Methods We used syngeneic murine models of extensive metastatic lung adenocarcinoma and melanoma to evaluate CAR T cell therapy following tumor irradiation. CAR T cells targeting either model or endogenously expressed tumor antigens were infused after lymphodepletion. CAR T cell infiltration, cytotoxicity, and persistence were evaluated via bioluminescence imaging, histology, flow cytometry, and RNA sequencing. The role of dendritic cells (DC) was interrogated using Zbtb46-DTR and Batf3 –/– transgenic mice and ex vivo live-cell imaging.Results Tumor irradiation significantly enhanced early CAR T cell infiltration into tumors and induced a potent effector phenotype marked by cytolytic and metabolic gene programs. This was associated with clearance of tumor and long-term survival. CAR T cells unexpectedly also showed enhanced persistence that was critically dependent on DCs. Tumor irradiation promoted the trogocytic transfer of intact tumor surface antigens onto DCs that could then expand CAR T cells through the chimeric receptor. In the absence of functional DCs, tumor irradiation did not enhance CAR T cell persistence and tumors relapsed, highlighting the requirement for sustained DC-mediated CAR T cell activity for durable control. The impact of irradiation was robust even when using CAR T cells targeted endogenously expressed antigens with low or high tumor selectivity (EpCAM and GD2, respectively). Remarkably, enhanced local activity of CAR T cells was not associated with increased systemic toxicity even when targeting EpCAM, a target antigen expressed widely on normal tissues inside and outside of the irradiated field.Conclusions We resolve distinct effects of irradiation that overcome key barriers of CAR T cell therapy for solid tumor. By enhancing the local activity of CAR T cells, irradiation effectively widened the therapeutic window of CAR T cells by enabling robust tumor control with lower, and safer cell doses. These findings establish a compelling rationale for combining radiotherapy with CAR T cell therapy when treating advanced solid tumors.References Albelda SM. CAR T cell therapy for patients with solid tumours: key lessons to learn and unlearn. Nat Rev Clin Oncol. 2024;21(1):47–66.Haas AR, Tanyi JL, O’Hara MH, Gladney WL, Lacey SF, Torigian DA, et al. Phase I study of lentiviral-transduced chimeric antigen receptor-modified T cells recognizing mesothelin in advanced solid cancers. Molecular Therapy [Internet] 2019 Nov 6;27(11):1919–29. Available from: https://doi.org/10.1016/j.ymthe.2019.07.015 Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Molecular Therapy [Internet] 2010 Feb 8;18(4):843–51. Available from: http://dx.doi.org/10.1038/mt.2010.24Ethics Approval Vertebrate animal experiments performed under the following protocol IACUC-2018-0081 approved by the Institutional Animal Care and Use Committee. The reference number of the OLAW approved Animal Welfare Assurance of Icahn School of Medicine at Mount Sinai is D16-00069 (A3111-01).",
  "authors": [
    {
      "affiliations": [
        "Icahn School of Medicine at Mount Sinai, New York, NY, USA"
      ],
      "name": "Sophia Navarre"
    },
    {
      "affiliations": [
        "Icahn School of Medicine at Mount Sinai, New York, NY, USA"
      ],
      "name": "Maki Ishibashi"
    },
    {
      "affiliations": [
        "Icahn School of Medicine at Mount Sinai, New York, NY, USA"
      ],
      "name": "Achuth Nair"
    },
    {
      "affiliations": [
        "Icahn School of Medicine at Mount Sinai, New York, NY, USA"
      ],
      "name": "Laszlo Halasz"
    },
    {
      "affiliations": [
        "OverT Bio, New York, NY, USA"
      ],
      "name": "Ivan Reyes-Torres"
    },
    {
      "affiliations": [
        "Icahn School of Medicine at Mount Sinai, New York, NY, USA"
      ],
      "name": "Matthew D Park"
    },
    {
      "affiliations": [
        "Icahn School of Medicine at Mount Sinai, New York, NY, USA"
      ],
      "name": "Raphaël Mattiuz"
    },
    {
      "affiliations": [
        "Icahn School of Medicine at Mount Sinai, New York, NY, USA"
      ],
      "name": "Meriem Belabed"
    },
    {
      "affiliations": [
        "Icahn School of Medicine at Mount Sinai, New York, NY, USA"
      ],
      "name": "Jessica Le Berichel"
    },
    {
      "affiliations": [
        "CUIMC, New York, NY, USA"
      ],
      "name": "Annalisa Cabriolu"
    },
    {
      "affiliations": [
        "Icahn School of Medicine at Mount Sinai, New York, NY, USA"
      ],
      "name": "Miriam Merad"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Michel Sadelain"
    },
    {
      "affiliations": [
        "Icahn School of Medicine at Mount Sinai, New York, NY, USA"
      ],
      "name": "Jalal Ahmed"
    }
  ],
  "title": "667 Dendritic cells accelerate CAR T cells in irradiated tumors through chimeric synapses",
  "uid": "2d7287cd-ba7f-5c1b-a985-c0373d1cf71f"
}