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Published on: February 16, 2015
Transient CAR T cells with specificity to oncofetal glycosaminoglycans in solid tumors
Nastaran Khazamipour1,2, Htoo Zarni Oo1,2,3, Nader Al-Nakouzi1,2
1Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
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 transient 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 unarmed 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 the survival of tumor-bearing mice. Thus, our work indicates that cancer-restricted glycosaminoglycans may be exploited as potential targets for CAR T cell therapy.
Insights
Researchers developed chimeric antigen receptor (CAR) T cells targeting cancer-specific chondroitin sulfate (CS). Armed with specific lectins, these CAR T cells effectively eliminated tumors in vitro and in vivo, showing promise for immunotherapy.
Area of Science:
- Immunology
- Oncology
- Glycobiology
Background:
- Glycosaminoglycans (GAGs) are challenging immunotherapy targets due to complex glyco-epitopes.
- Oncofetal chondroitin sulfate (CS) is expressed on solid tumors but typically restricted to the placenta.
Purpose of the Study:
- To design and evaluate chimeric antigen receptor (CAR) T cells targeting oncofetal CS.
- To assess the efficacy of VAR2CSA-lectin-armed CAR T cells against tumors expressing oncofetal CS.
Main Methods:
- Development of transient CAR T cells with specificity for oncofetal CS.
- Arming CAR T cells with recombinant VAR2CSA lectins (rVAR2) for tumor cell targeting.
- In vitro and in vivo evaluation of CAR T cell activation, cytotoxicity, and anti-tumor effects.
Main Results:
- VAR2-armed CAR T cells demonstrated robust activation and eliminated diverse tumor cell types in vitro.
- CAR T cell cytotoxicity was tunable by the concentration of rVAR2.
- In vivo studies showed armed CAR T cells targeting bladder tumors and improving survival in mice.
Conclusions:
- Transient CAR T cells armed with rVAR2 can effectively target and eliminate tumors expressing oncofetal CS.
- Cancer-restricted GAGs represent a viable target for novel CAR T cell-based immunotherapies.
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