The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity

Abstract

Engineering T cells with chimeric antigen receptors (CARs) is an effective method for directing T cells to attack tumors, but may cause adverse side effects such as the potentially lethal cytokine release syndrome. Here the authors show that the T cell antigen coupler (TAC), a chimeric receptor that co-opts the endogenous TCR, induces more efficient anti-tumor responses and reduced toxicity when compared with past-generation CARs. TAC-engineered T cells induce robust and antigen-specific cytokine production and cytotoxicity in vitro, and strong anti-tumor activity in a variety of xenograft models including solid and liquid tumors. In a solid tumor model, TAC-T cells outperform CD28-based CAR-T cells with increased anti-tumor efficacy, reduced toxicity, and faster tumor infiltration. Intratumoral TAC-T cells are enriched for Ki-67+ CD8+ T cells, demonstrating local expansion. These results indicate that TAC-T cells may have a superior therapeutic index relative to CAR-T cells.

B7-H7 (HHLA2) inhibits T-cell activation and proliferation in the presence of TCR and CD28 signaling

“…Their studies demonstrated that the use of OKT3 in this setting produced poor proliferation and cytokine production, and that UCHT1 TACs demonstrated superior performance in preclinical models of solid and hematological tumors. 31 In our study, we demonstrate that B7-H7 cotreatment with OKT3 has opposing outcomes when compared with cotreatment with UCHT1, which could be explained by discrepancies in epitope specificity and the strength of the signal delivered by the different α-CD3 clones. In addition, as discussed later, we believe that OKT3 is the superior clone that should be used in these assays, as it reflects the biological outcomes of in vitro physiological assays.…”

Emerging agents and regimens for multiple myeloma

“…Researchers speculated that CAR-T cell toxicity is related to the synthetic nature of the receptor design. Therefore, a new type of CAR-T cells has been designed with an MHC-independent receptor T cell antigen coupler, which can co-opt the endogenous TCR and exert antitumor effect with fewer toxic reactions [ 116 ]. Other AEs include persistent cytopenia, hypogammaglobulinemia, and inflammation; all these could be managed through appropriate supportive treatments but need close monitoring.…”

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…Also, receptor potentiation by proteolysis of a small masking tag degraded in the presence of specific proteases expressed in the tumor microenvironment was elegantly demonstrated for an EGFR-specific CAR [300]. Recently, Helsen et al reported the use of a T-cell antigen coupler (TAC) chimeric receptor [301] which consists of a double targeting moiety: an antigen-specific scFv followed by a CD3-activating scFv built on a CD4 scaffold. Such TAC could recognize a defined tumor antigen on the target cell using the endogenous TCR signaling pathway rather than an artificial signal mediated by classical CD28/CD3z signaling moiety.…”