HLA-independent T cell receptors for targeting tumors with low antigen density

HLA-independent T cell receptors, in which the heavy and light chains of a chimeric antigen receptor are incorporated into the endogenous T cell receptor locus, are more effective than CD28-based chimeric antigen receptors at targeting tumors with low antigen expression. Chimeric antigen receptors (CARs) are receptors for antigen that direct potent immune responses. Tumor escape associated with low target antigen expression is emerging as one potential limitation of their efficacy. Here we edit the TRAC locus in human peripheral blood T cells to engage cell-surface targets through their T cell receptor-CD3 complex reconfigured to utilize the same immunoglobulin heavy and light chains as a matched CAR. We demonstrate that these HLA-independent T cell receptors (HIT receptors) consistently afford high antigen sensitivity and mediate tumor recognition beyond what CD28-based CARs, the most sensitive design to date, can provide. We demonstrate that the functional persistence of HIT T cells can be augmented by constitutive coexpression of CD80 and 4-1BBL. Finally, we validate the increased antigen sensitivity afforded by HIT receptors in xenograft mouse models of B cell leukemia and acute myeloid leukemia, targeting CD19 and CD70, respectively. Overall, HIT receptors are well suited for targeting cell surface antigens of low abundance.

Automated summary

HLA-independent T cell receptors (HIT receptors) are a novel type of chimeric antigen receptors that can effectively target tumors with low antigen expression, surpassing the sensitivity of CD28-based receptors. They offer high antigen sensitivity and can recognize tumors beyond the capabilities of other CAR designs. The functional persistence of HIT T cells can be enhanced by coexpression of CD80 and 4-1BBL. HIT receptors have been validated in xenograft mouse models, targeting CD19 and CD70 in B cell leukemia and acute myeloid leukemia, respectively.