Synthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response
Baeuerle PA, Ding J, Patel E, Thorausch N, Horton H, Gierut J, Scarfo I, Choudhary R, Kiner O, Krishnamurthy J, Le B, Morath A, Baldeviano GC, Quinn J, Tavares P, Wei Q, Weiler S, Maus MV, Getts D, Schamel WW, Hofmeister R.
Nat Commun. online article
We study the mechanisms with which the T cell receptor is activated by ligand binding. One plan was to cooperate with the company TCR2 Therapeutics, to use our knowledge, in order to develop a new design of chimeric receptors for cancer immunotherapy. The first generation of these engineered receptors has now been published. We show that an intact TCR complex can be effectively reprogrammed for cancer therapy by recombinantly fusing an anti-CD19 scFv to its TCRα, TCRβ, CD3γ, CD3δ, or CD3ε subunit. Respective scFv-TCR fusion constructs (termed TRuCs) were integrated into the TCR complex and expressed on the surface of T cells. In the presence of CD19-positive tumor cells, fusion constructs based on CD3ε and CD3γ could specifically and potently activate T cells. Despite the absence of extra signaling domains, TRuC-T cells showed similar in vitro cytotoxicity as CD28- and 4-1BB-based anti-CD19 CAR-T cells. A single CD3ε-TRuC-T cell dose greatly extended the survival of mice with Nalm6 leukemia. In a subcutaneous Raji tumor model, CD3ε-TRuC-T cells outperformed CAR-T cells in terms of anti-tumor activity. Our novel technology for genetically engineering T cells provides an alternative to CARs that can engage the physiological and broad signaling capacity of the entire TCR complex.