Clinical trials of NK cells for cancer

Natural killer (NK) cells mediate the response to stress-inducing nonspecific lysis of targets and production of inflammatory cytokines. They can mediate potent antitumor responses and play an important role in immune surveillance. Their effector function is governed by a complex balance of activating and inhibitory signals transferred via several classes of receptors, a number of which recognize "self" MHC class I antigens. Self-tolerance is mediated by inhibitory killer immunoglobulin-like receptors (KIRs) and other receptors, which transmit signals that interrupt the cytolytic pathway upon binding of their cognate class I HLA ligands. The loss of KIR-ligand expression by infected or malignant targets renders them susceptible to NK cell lysis, particularly when the targets also present ligands for activating receptors. NK cells, which can be easily isolated in high quantity from donor lymphapheresis products, do not cause graft vs. host disease (GVHD). Thus NK cells are an attractive cell population to exploit for antitumor immunotherapy. The effector response exhibited by NK cells varies widely depending upon the circumstances of their development and education, on their receptor profile, on the target's receptor ligand expression and by signals received from other immune cells. NK cell activity can be manipulated for therapeutic intent against several tumor, including hematologic malignancies and numerous solid tumor, including melanoma, renal cell carcinoma, ovarian cancer and neuroblastoma. Autologous NK cells can be directed against tumors by blocking inhibitory receptors, by increasing the expression of activating receptor ligands on tumors and by targeting NK antibody-dependent cellular cytotoxicity (ADCC) against those receptors with specific antibodies. Alloreactive NK cells developing after allogeneic HCT or after adoptive transfer have powerful antitumor activity.