Targeted delivery of interferon-gamma by synNotch T cells sensitizes neuroblastoma cells to T cell-mediated killing

Downregulation of HLA is one of the most common tumor escape mechanisms by enabling tumors to persist in the presence of tumor-reactive T cells. HLA loss is particularly common in children with high-risk neuroblastoma, who have a 50% long-term survival despite dose-intensive regimens. We have now developed an approach for the targeted induction of HLA to restore sensitivity of neuroblastoma cells to T cell-mediated killing. Using synNotch technology, we have generated T cells that, upon binding of the neuroblastoma surface antigen GD2, secrete IFN-{gamma} without conferring direct cytotoxic activity (snGD2i). Treatment with snGD2i cells induces high and durable expression of HLA on neuroblastoma cells in vitro and in vivo and restores sensitivity to TCR-transgenic T cells targeting neuroblastoma-specific antigens. In contrast, treatment does not lead to upregulation of immune checkpoints or systemically increased levels of IFN-{gamma}. Targeted delivery of IFN-{gamma} using snGD2i cells is a promising new strategy to address immune escape in neuroblastoma. STATEMENT OF SIGNIFICANCEHLA loss remains one of the most common and unsolved immune escape mechanisms in cancer cells. We have now developed a cell-based approach for the targeted upregulation of HLA on tumor cells, which efficiently sensitizes the malignant cells to killing by tumor-reactive T cells.