bioRxiv : the preprint server for biology · 2026
Low-dose radiopharmaceutical therapy enhances the efficacy of B7-H3 CAR T cells in murine metastatic neuroblastoma.
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Shea Amanda G, Ollendorff Andrew, Wilke Andreanna, Shi Lei, Erbe Amy K, Ansari Israrul H, Bio Idrissou Malick, Kwon Ohyun, Comas Rojas Hansel, Barisa Marta, Anderson John, Eickhoff Jens C, Ong Irene, Richards Rebecca M, Sondel Paul M, Capitini Christian M, Hernandez Reinier, Bednarz Bryan P, Weichert Jamey P, Morris Zachary S, Sodji Quaovi H
Аннотация
BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy has had clinical success in hematologic malignancies, but limited efficacy is seen in solid tumors. In this study, we investigated whether systemic CAR T cell therapy could be enhanced in metastatic models of neuroblastoma when combined with radiopharmaceutical therapy (RPT).
METHODS: Non-irradiated or irradiated tumor cells were co-cultured with CAR T cells (1:1) in vitro and supernatant media was subsequently collected for cytokines analyses. CAR T cells' phenotypes were characterized by flow cytometry including checkpoint marker expression. Xenograft models of metastatic neuroblastoma were generated in NOD- Rag1 null IL2rg null (NRG) mice. Tumor-bearing mice received 1.8 Gy of radiation delivered by 177 Lu-NM600 RPT five days after tumor implantation. Nine days after RPT, 4 x 10 6 CAR T cells were administered intravenously. To evaluate tumor burden, mice were imaged weekly for 4 weeks.
RESULTS: In models of metastatic neuroblastoma, 177 Lu-NM600 RPT significantly increased overall survival when combined with CAR T cell therapy in vivo . Pre-treatment of tumor cells with 177 Lu also significantly increased CAR T cell cytotoxicity while decreasing production of IL-4 and IL-10 in vitro . Co-culture of CAR T cells with irradiated tumors led to increases in PD-1 + TIM3 + LAG3 + T cells, suggesting that further combination with immune checkpoint inhibitors may enhance clinical efficacy.
CONCLUSIONS: Our findings demonstrate that low-dose RPT can potentiate the anti-tumor efficacy of CAR T cells in metastatic neuroblastoma. To our knowledge, this is the first report of dosimetry-based RPT being combined with CAR T cells in a metastatic solid tumor setting. These findings underscore the potential of combining RPT and CAR T cells to overcome the unique challenges of solid tumors, particularly when treating metastatic disease.
METHODS: Non-irradiated or irradiated tumor cells were co-cultured with CAR T cells (1:1) in vitro and supernatant media was subsequently collected for cytokines analyses. CAR T cells' phenotypes were characterized by flow cytometry including checkpoint marker expression. Xenograft models of metastatic neuroblastoma were generated in NOD- Rag1 null IL2rg null (NRG) mice. Tumor-bearing mice received 1.8 Gy of radiation delivered by 177 Lu-NM600 RPT five days after tumor implantation. Nine days after RPT, 4 x 10 6 CAR T cells were administered intravenously. To evaluate tumor burden, mice were imaged weekly for 4 weeks.
RESULTS: In models of metastatic neuroblastoma, 177 Lu-NM600 RPT significantly increased overall survival when combined with CAR T cell therapy in vivo . Pre-treatment of tumor cells with 177 Lu also significantly increased CAR T cell cytotoxicity while decreasing production of IL-4 and IL-10 in vitro . Co-culture of CAR T cells with irradiated tumors led to increases in PD-1 + TIM3 + LAG3 + T cells, suggesting that further combination with immune checkpoint inhibitors may enhance clinical efficacy.
CONCLUSIONS: Our findings demonstrate that low-dose RPT can potentiate the anti-tumor efficacy of CAR T cells in metastatic neuroblastoma. To our knowledge, this is the first report of dosimetry-based RPT being combined with CAR T cells in a metastatic solid tumor setting. These findings underscore the potential of combining RPT and CAR T cells to overcome the unique challenges of solid tumors, particularly when treating metastatic disease.