Customizing Functionality and Payload Delivery for Receptor-Engineered T Cells

Abstract

Adoptive immunotherapy using receptor engineering to achieve specific tumor targeting by T cells holds much promise for advancing cancer therapy. Here, two studies by Boice et al. and Roybal et al. provide distinct and potentially complimentary approaches to improve the efficacy and curb potential toxicities of this approach.

Figure 1.. Customized Sensing and Transcriptional Responses Using the synNotch Receptor in T Cells

(A) The synthetic Notch (synNotch) receptor is built upon a central core derived from the wild-type Notch receptor. This includes a transmembrane (TM) domain, two regulated proteolytic cleavage domains, and a series of Lin 12-Notch repeats and heterodimerization domains that prevent spontaneous receptor activation. (B) Both the extra- and intra-cellular domains of Notch can be replaced in a synNotch receptor with diverse antigen recognition domains, such as the single-chain variable fragments (scFvs) of an antibody and an artificial transcription factor, such as Gal4-VP64. (C and D) (C) In contrast with constitutive expression of transgenes using the 5’-long terminal repeat (LTR) of a retrovirus, (D) the synNotch receptor allows for customized therapeutic responses triggered in a ligand-dependent manner. This could include the release of specific cytokines, activation of lineage-specific transcription factors, triggering of defined effector mechanisms, or secretion of large macromolecules such as antibodies. CTLA4, cytotoxic T-lymphocyte associated protein 4; DR4, death receptor 4; PD1, programmed cell death 1; PEST, peptide sequence rich in proline, glutamate, serine, and threonine; UAS, upstream activation sequence.