With these advances, we hope to see the Bi-ChTCRs move to the clinic, hoping to generate long-lasting responses and prevent relapses in cancer patients.

@fredhutch.bsky.social
#CancerResearch #Immunotherapy #TCellTherapy #Bi-ChTCR #SyntheticImmunity

Finally, we demonstrated that eliminating the endogenous TCR chains – here using base editing – was essential to maximize the expression level and therefore antigen sensitivity of this emerging class of HLA-independent receptors, and should be taken into consideration for clinical applications.

While bispecific CARs are often compromised for antigen binding and for signaling, Bi-ChTCRs maintained exquisite antigen sensitivity! We believe this is due to the multimeric assembly of the TCR complex where each TCR chain need to pair for expression at the membrane yet function independently!

Furthermore, the Bi-ChTCR platform was resilient as we were able to extend our findings initially targeting CD19 and CD22 antigens to Bi-ChTCRs targeting multiple pairs of Multiple Myeloma antigens.

T cells equipped with Bi-ChTCRs demonstrated “true” bispecificity in vitro and could eliminate tumors heterogenous for antigen expression and antigen levels in mouse models outperforming bispecific CARs or a mixture of monospecific CAR products.

These bispecific ChTCRs recapitulated the TCR structure pairing with CD3 subunits, formed bull’s eye immune synapses and demonstrated potent TCR-like proximal signaling leading to superior antigen sensitivity in comparison to classical CAR designs and previously described HLA-independent receptors.