Cell therapy based on the chimeric receptor NKG2D
A Perez Martinez(1)
1:Hospital La Paz
Natural killer group-2 member D (NKG2D) is an activating receptor expressed in cytotoxic lymphocytes that plays an important role in anti-tumor immunosurveillance. By recognition of the stress-inducible ligands MICA, MICB, and ULBP1-6, which are expressed on the surface of various tumor cells, including T, B, and myeloid leukemia blasts, the NKG2D receptor modulates lymphocyte activation and promotes target cell elimination. NKG2D chimeric antigen receptor (CAR) T cells have shown potent anticancer effects against various cancer types as pediatric sarcomas in preclinical studies and also have demonstrated safety and tolerability in relapsing/refractory (r/r) acute myeloid leukemia and myelodysplastic syndrome in adult patients. The use of allogeneic CAR T cells from healthy donors could be an attractive alternative because it presents many potential advantages, such as its immediate availability for all patients regardless of the hematological situation, standardization of the CAR T cell product, and reduced costs. However, the use of allogeneic T cells can cause undesirable graft versus host reactions and host immune rejection of infused non-HLA matched T-cells. We explore the use antigen-experienced memory T cells for CAR transduction as haploidentical CD45RA⁺ depleted T cells. The immunoescape mechanisms to NKG2D approach may include release of NKG2DL, NKG2DL downregulation, NKG2D recognition on immune synapses, and inactivation by the immunosuppressive bone marrow niche, and leukemic cell clone selection.