Removal of CAR-T cells is a useful way to limit the adverse effects post CAR-T cell therapy; however, it terminates the anti-tumor clinical effects at the same time. Off-tumor toxicity can be inhibited by enhancing the specificity of CAR-T cells. With proper design, CAR-T cells are able to exhibit activity only in response to a particular combination of dual tumor-associated antigens that are co-expressed by tumor targets. The dual CAR-T cells express two kinds of CARs, one of which recognizes and binds to one tumor-associated antigen and transmits only the primary signal, while the other recognizes a distinct tumor antigen and transmits the co-stimulatory signal. Therefore, dual CAR-T cells show activity only under the presence of both targets on the tumor and thus possess improved safety.
For example, one type of design for dual CAR-T cells is that T cells co-expressing anti-ErbB2 and anti-MUC1 specific CARs use CD3ζ and CD28 signaling pathways, respectively. These dual CAR-T cells kill ErbB2+ tumor cells efficiently and proliferate in conditions that requires co-expression of MUC1 and ErbB2 by target cells. In another example, T cells are genetically modified to co-express signal 1 (Anti-Meso scFv-CD3ζ) and signal 2 (Anti-Fra scFv-CD28) CARs. These CAR-T cells show weak cytokine secretion against target cells expressing only one tumor-associated antigen in vitro, which is similar to first generation CAR-T cells bearing CD3ζ only, but demonstrate enhanced cytokine secretion upon encountering natural or engineered tumor cells co-expressing both antigens. The dual CAR approach potentiates the therapeutic efficacy of CAR-T cells against cancers while minimize parallel reactivity against normal tissues bearing single antigen.
Marked chimeric antigen receptor models and concepts
Nature Reviews Cancer. 2016.
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