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khazamipour, Nastaran

University of British Columbia

The malaria parasite Plasmodium falciparum expresses VAR2CSA proteins on the surface of infected red blood cells that bind a distinct type of chondroitin sulfate (CS) glycosaminoglycan (GAG) exclusively present in the placenta. This interaction is the key underlying cause of pregnancy-associated malaria outbreaks in endemic regions of the world. Interestingly, placental-type CS GAGs become re-expressed in multiple human cancers as a secondary oncofetal CS (ofCS) modification to proteoglycans. I used this specific feature of malaria tropism to develop novel cancer diagnostic and therapeutic strategies. By incorporating the recombinant VAR2CSA protein (rVAR2) sequence into a chimeric antigen receptor (CAR), I was able to develop a universal anti-ofCS CAR (VAR2-CAR) with affinity for tumor cells expressing ofCS. In order to obtain a strong safety profile, I designed a switch-CAR system in which a non-binding CAR could be secondarily ‘armed’ with a rVAR2-switch molecule producing functional ofCS-reactive sVAR2-CAR T cells. The population of armed CAR T cells was controlled by the concentration of the switch molecule and importantly, halting the addition of the switch molecule through clonal expansion, cleared the armed population of sVAR2-CAR T cells from the organism post-treatment. Co-culturing the sVAR2-CAR T cells with human tumor cells resulted in activation of the CAR T cells as assessed by expression of activation markers and production of cytokines. The sVAR2-CAR T cells were able to engage diverse ofCS-positive tumor cells and effectively eliminate them. Finally, two treatments of sVAR2-CAR T cells were able to markedly decrease tumor burden in a murine xenograft model of bladder cancer. My data provide proof-of-concept for an rVAR2-armed CAR-T cell approach to treat ofCS-positive cancers. In addition, ofCS is an efficient and specific target for isolating tumor cells from blood samples. A variety of ofCS positive cancer cells spiked into the blood were successfully isolated by employing rVAR2-coated magnetic beads. Combining rVAR2-technology and nucleic acid detection, I was able to develop a new strategy for isolating and identifying circulating tumor cells (CTC). Taken together, the exclusive expression of ofCS on tumors and the high specificity of rVAR2 to ofCS, can be complementary exploited for tumor diagnosis and treatment.

Text

2025-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/80039

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/