Low-dose radiopharmaceutical therapy enhances the efficacy of B7-H3 CAR T cells in murine metastatic neuroblastoma
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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.
