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Smarter™ Dual CAR Construction Service

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

Marked chimeric antigen receptor models and concepts
Nature Reviews Cancer. 2016.

As the leading biotech company in CAR-T cell therapy, Creative Biolabs focuses on some urgent questions and try our best to overcome these problems. We have developed multiple novel 4th generation CAR technologies and provide SmarterTM Dual CAR construction service to help our clients to develop a safer CAR-T therapy with improved anti-tumor effects.

References

  1. Fesnak, et al. "Engineered T cells: the promise and challenges of cancer immunotherapy." Nature Reviews Cancer 16.9 (2016): 566-581.
  2. Lanitis, et al. "Chimeric antigen receptor T cells with dissociated signaling domains exhibit focused antitumor activity with reduced potential for toxicity in vivo." Cancer immunology research 1.1 (2013): 43-53.
  3. Wilkie, et al. "Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling." Journal of clinical immunology 32.5 (2012): 1059-1070.

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