Multivalent RNA CAR-T cell for malignant glioma

The therapeutic use of chimeric antigen receptor T cells has achieved significant success in the treatment of B cells malignancies. Despite promising results in mouse tumor models, a similar outcome hasn’t yet been observed in solid tumors. Specifically, in glioblastoma (GBM) several clinical trials only showed a modest efficacy, partly due to the high tumor heterogeneity. In this setting, we aim to develop an "à-la-carte" CAR-T cell strategy that targets a panel of GBM antigens. We use transiently expressed RNA CAR-T cells, allowing to acheive the dual goal of reducing potential side effects while delivering multiple CAR-T cell infusions. Through a phage display screening, we generated various different new scFv against GBM associted cell surface targets and cloned them into an RNA CAR plasmid. Then we selected the ones with better cytotoxic activity against a GBM target expressing cell lines derived from patients operated in our institution. Using triple reporter Jurkat cell lines we show that CAR transient expression is able to be sustained for at least 7 days whitout toxic signaling. In an orthotopic allogeneic tumor model using NSG mice, a single dose of our lead CAR-T cell product is able to significantly increase the mice’s overall survival. Our results point to validating the use of RNA CARTs as an attractive new manufacturing platform in the GBM setting.

 

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