Rodriguez and Edinger et al. showed that pre-treatment with VLA-4-targeted, low-dose radiopharmaceutical therapy (RPT) using [67Cu] Cu-LLP2A enhanced GD2 or B7-H3 CAR T cell efficacy, resulting in significant tumor regression in xenogeneic, preclinical neuroblastoma models. The mechanism of action varied with tumor radiosensitivity. In radiosensitive tumors, RPT was directly tumoricidal and enhanced CAR T cell efficacy via TNF-α, leading to paracrine T cell activation. In radioresistant tumors, RPT remodeled the TIME by decreasing the number of M2-like TAMs and stimulating the formation of enriched cytotoxic CD4+ and CD8+ T cell clusters.
Contributed by Katherine Turner
ABSTRACT: Chimeric antigen receptor (CAR) T cell therapy has limited efficacy against solid tumors such as neuroblastoma (NB). Key obstacles include extensive tumor burden and the presence of an immunosuppressive tumor microenvironment (TME). We employ targeted radiopharmaceutical therapy (RPT) using [(67)Cu]Cu-LLP2A and show that it potentiated the anti-tumor activity of CAR T cells in radio-sensitive and radio-resistant NB models via distinct mechanisms. In radio-sensitive NB, RPT is directly tumoricidal while also enhancing CAR T cell efficacy through pro-immune pathways, most notably via the TNF-_ pathway, leading to paracrine activation of T cells. In radio-resistant NB, RPT improves CAR T cells by remodeling the myeloid compartment in the TME and increasing the formation of immunological niches of cytotoxic CD8(+) GZMB(+) and CD4(+) GZMB(+) CAR T cells. While neither treatment modality alone can effectively treat NB, the combination of VLA-4-targeted RPT and GD2 or B7-H3 CAR T cells augments anti-tumor efficacy, resulting in marked tumor regression in preclinical NB models.
Author Info: (1) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (2) Department of Radiation Oncology, Univer
Author Info: (1) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (2) Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA. (3) Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA; Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA. (4) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (5) Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (6) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (7) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (8) Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (9) Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (10) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (11) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (12) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (13) Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA. (14) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (15) Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (16) Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA. (17) Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA. (18) Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (19) Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (20) Rutgers Cancer Institute, New Brunswick, NJ, USA; Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA. (21) Departments of Chemistry and Radiology, University of Missouri, Columbia, MO, USA. (22) Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: freddy.escorcia@gmail.com. (23) Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA; Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Biomedical Engineering, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: patelr20@upmc.edu. (24) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: hongharosa.nguyen@nih.gov.
