Conditional CAR T cells with specificity to oncofetal glycosaminoglycans in solid tumors
Khazamipour, N.; Oo, H. Z.; Al-Nakouzi, N.; Marzban, M.; Khazamipour, N.; Robert, M. E.; Farivar, N.; Moskalev, I.; Lo, J.; Ghaidi, F.; Nelepcu, I.; Moeen, A.; Truong, S.; Dagil, R.; Choudhary, S.; Gustavsson, T.; Zhai, B.; Heitzender, S.; Salanti, A.; Sorensen, P. H.; Daugaard, M.
Show abstract
Glycosaminoglycans are often deprioritized as targets for synthetic immunotherapy due to the complexity of glyco-epitopes and limited options for obtaining specific subtype-binding. Solid tumors express proteoglycans that are modified with oncofetal chondroitin sulfate (CS), a modification normally restricted to the placenta. Here, we report the design and functionality of conditional chimeric antigen receptor (CAR) T cells with selectivity to oncofetal CS. Following expression in T cells, the CAR could be armed with recombinant VAR2CSA lectins (rVAR2) to target tumor cells expressing oncofetal CS. While un-armed CAR T cells remained inactive in the presence of target cells, VAR2-armed CAR T cells displayed robust activation and the ability to eliminate diverse tumor cell types in vitro. Cytotoxicity of the CAR T cells was proportional to the concentration of rVAR2 available to the CAR, offering a potential molecular handle to finetune CAR T cell activity. In vivo, armed CAR T cells rapidly targeted bladder tumors and increased survival of tumor-bearing mice. Thus, our work indicates that cancer-restricted glycosaminoglycans can be exploited as potential targets for CAR T cell therapy.
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