Immunostimulatory RNA Expression Enhances CAR T-cell Function In Vivo

Although chimeric antigen receptor (CAR) T-cell therapies have been demonstrated to be efficacious against many blood cancers, insufficient CAR T-cell expansion and persistence in the tumor microenvironment and CAR antigen loss can limit efficacy. Johnson and colleagues engineered CAR T cells to express not only a tumor-targeting CAR, but also a highly structured immunostimulatory RNA, RN7SL1, which can activate RIG-I–MDA5 signaling to produce an IFN response in myeloid and dendritic cells that can then promote T-cell priming and activation. Importantly, providing a basis for expressing RN7SL1 specifically in CAR T cells, in vivo experiments confirmed that sensing of RN7SL1 by immune cells rather than cancer cells was important for promoting antitumor immunity; RN7SL1 sensing by cancer cells, in contrast, promoted tumor progression and immune suppression. After expansion, CAR T cells engineered from healthy human donor T cells to express RN7SL1 along with a CD19-targeting CAR comprised a greater proportion of effector memory CAR T cells than those not expressing RN7SL1. In mouse xenograft models, this corresponded to enhanced tumor control and greater tumor infiltration by RN7SL1-expressing CAR T cells. Mechanistically, CAR T cells appeared to deliver RN7SL1 selectively to endogenous immune cells, rather than to cancer cells, via extracellular vesicles. In immunocompetent syngeneic mouse tumor models, immune checkpoint blockade synergized with RN7SL1-expressing CAR T cells to produce increased CAR T-cell efficacy and greater immune cell infiltration in tumors. Additionally, RN7SL1 delivery by CAR T cells promoted CD8⁺ T-cell function, increasing the proportion of effector memory–like endogenous CD8⁺ T cells and reducing the number of exhausted endogenous CD8⁺ T cells, even in a model of antigen loss. RN7SL1 could also be codelivered with peptide antigens to increase immunogenicity. Collectively, this work demonstrates that the immunostimulatory noncoding RNA RN7SL1 can promote CAR T-cell function and promote an endogenous anti-tumor immune response even in the setting of CAR antigen loss or poor immunogenicity, suggesting that further study of the effects of RN7SL1 expression by CAR T cells is justified.

Johnson LR, Lee DY, Eacret JS, Ye D, June CH, Minn AJ. The immunostimulatory RNA RN7SL1 enables CAR-T cells to enhance autonomous and endogenous immune function. Cell 2021 Aug 30 [Epub ahead of print].

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