T-cell receptor engineering of primary NK-cells to therapeutically target tumours and tumour immune evasion

Abstract TCR-engineered cells can be powerful tools in the treatment of malignancies. However tumor-resistance by HLA-class I downregulation can negatively-impact the success of any TCR-mediated cell therapy. Allogeneic NK-cells have demonstrated efficacy and safety against malignancies without inducing GvHD highlighting the feasibility for an “off the shelf” cellular therapeutic. Furthermore, primary NK-cells, sourced from the peripheral blood or umbilical-cord blood, can target tumours using a broad array of intrinsic activation mechanisms. Here, we developed a unique NK:TCR cell therapy from peripheral blood derived NK-cells, which enhances NK-efficacy against tumours through additional TCR-mediated lysis. Upon loss of HLA-class I, NK:TCR will lyse the resistant tumour cells in an NK-mediated manner. Our NK:TCR technology is the first cellular therapy which incorporates TCR-based targeting of tumours and the associated TCR immune-evasion.