Engineering self-propelled tumor-infiltrating CAR T cells using synthetic velocity receptors

Inventors & their inventions

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T-cells exhibit low and high migration phenotypes depending on cell density in 3D collagen gels. At high density, T-cells secrete cytokines like IL5, TNFa, IFNg, and IL8 that shift cells to a high migration state.

The authors used this by engineering "velocity receptors" (VRs) that bind these cytokines and signal through their receptors, pushing CAR T cells into a highly migratory state even at low density.

VR-CAR T cells showed greater infiltration and anti-tumor effects compared to regular CAR T cells alone in mouse models of pancreatic, lung, and ovarian cancer. VR-CAR T cells penetrated deep into tumor cores whereas regular CAR T cells remained largely at the periphery. In an ovarian cancer model, VR-CAR T cell therapy significantly increased mouse survival compared to CAR T alone. This demonstrates that enhancing migration signaling via receptors that take advantage of T cell-secreted cytokines can improve CAR T cell infiltration and efficacy against solid tumors. With their highly modular VELOCIREPTORS, they can generate >30K different types of self-propelled CAR-T cells designed to infiltrate solid tumors. Testing 5 in mouse models of pancreatic/ovarian/lung cancer, three cancers with poor survival rates. The VR approach pushes CAR T cells into a highly migratory phenotype to facilitate tumor infiltration.

https://www.biorxiv.org/content/10.1101/2023.12.13.571595v2