Research Demonstrates Novel HIT Receptor Enhances T Cell Antigen Sensitivity and Elicits Superior Tumor Control

The journal Nature Medicine recently published a study in which researchers developed a novel receptor to enhance recognition of tumors by engineered T cells, addressing an underlying cause for relapsed tumors in patients after chimeric antigen receptor (CAR) therapy. The study demonstrates high antigen sensitivity of HLA-independent T-cell (HIT) receptors, created by editing the TCR Alpha Constant chain (TRAC) locus in human peripheral blood Tcells.

Low antigen expression
One major limitation of CARs is antigen escape, when a tumor no longer expresses the antigen detectable by the CARs or expresses them at a very low level; CARs with heightened sensitivity to low-expression level antigens boosts the efficacy of otherwise promising T-cell therapies.

In the study, conducted by researchers at New York’s Memorial Sloan Kettering Cancer Center (MSKCC), researchers produced HIT T-cells and analyzed them in animal models:

• HIT T-cells were engineered from human peripheral blood T-cells by inserting variable region genes in the TRAC locus, endowing the cell with a single specificity for a target antigen such as CD19. Notably, this sensitivity was shown to be higher than traditional CARs for low levels of antigen expression (~20 CD19 molecules per cell), resulting in superior cytotoxicity and cytokine secretion.
• HIT Tcells outperformed traditional CAR T-cells in vivo in mouse models of B cell leukemia and acute myeloid leukemia, without costimulation. Coexpression of HIT with CD80 and 4-1BBL further augmented therapeutic activity and mouse survival.

HIT T-cells are a promising therapy for targeting cancer cell surface antigens with low abundance due to their sensitivity and persistence.

The team responsible for this important work includes MSKCC researcher and Mnemo Therapeutics scientific cofounder Michel Sadelain, M.D., Ph.D., MSKCC researcher and Mnemo scientific advisor Isabelle Rivière, Ph.D., as well as Justin Eyquem, Ph.D., University of California San Franciso and Mnemo scientific cofounder.