含 CD28 信号基序的嵌合 CD3ζ 链增强体外抗原特异性 IL-2 产生和人 TCR 工程化 T 细胞扩增

Gene-engineered T-cell products have been developed for immunotherapy to treat cancers, with great success observed in haematological malignancies but limited efficacy in treating solid cancers. TCR-engineered T cells utilize transferred TCRs targeting tumour-associated and cancer-specific peptides presented by MHC molecules.

The CD3 chains are part of the TCR-CD3 complex expressed by T cells and mediate signal transduction when the TCR binds to MHC-presented peptides. In this study, we explored whether co-stimulation domains, that were effective in improving the function of T cells engineered with chimeric antigen receptors (CARs), can be exploited to improve the functionality of TCR-engineered T cells.

We inserted the signalling domains of CD28 or 4-1BB at the membrane proximal or the membrane distal position of the intracellular tail of CD3 and engineered human T cells to express a specific TCR in combination with either modified CD3 or unmodified control. Antigen-specific in vitro stimulation assays revealed that T cells expressing CD3 constructs with CD28 signal domains displayed enhanced peptide-specific IL-2 production and, following repeated antigen stimulation, expanded to substantially greater numbers than T cells expressing unmodified CD3 .

Importantly, greater expansion seen with the CD28-containing did not result in any reduction of effector function as assessed by peptide-specific cytotoxicity and cytokine production. The data indicate that modification of the CD3 chain with a CD28 signal motif provides an opportunity to improve antigen-specific expansion and effector function of TCR-engineered T cells by combining signal 1 and co-stimulatory signal 2 in one molecular TCR-CD3 complex.