Infusions of Allogeneic Natural Killer Cells as Cancer Therapy

Abstract

Natural killer (NK) cells are normal white blood cells capable of killing malignant cells without prior sensitization. Allogeneic NK cell infusions are attractive for cancer therapy because of non-cross-resistant mechanisms of action and minimal overlapping toxicities with standard cancer treatments. Although NK therapy is promising, many obstacles will need to be overcome, including insufficient cell numbers, failure of homing to tumor sites, effector dysfunction, exhaustion, and tumor cell evasion. Capitalizing on the wealth of knowledge generated by recent NK cell biology studies and the advancements in biotechnology, substantial progress has been made recently in improving therapeutic efficiency and reducing side effects. A multipronged strategy is essential, including immunogenetic-based donor selection, refined NK cell bioprocessing, and novel augmentation techniques, to improve NK function and to reduce tumor resistance. Although data from clinical trials are currently limited primarily to hematologic malignancies, broader applications to a wide spectrum of adult and pediatric cancers are under way. The unique properties of human NK cells open up a new arena of novel cell-based immunotherapy against cancers that are resistant to contemporary therapies. Clin Cancer Res; 20(13); 3390-400. Ó2014 AACR.

Overexpression of KIR inhibitory ligands (HLA-I) determines that immunosurveillance of myeloma depends on diverse and strong NK cell licensing

“…Thus, differential expression of HLA among cancers could have contributed to the variety of models proposed to explain NK allo-reactivity in haploidentical SCT. 38 Certainly, our data and others. 27 demonstrate that myeloma-PCs, compared to normal lymphocytes and other hematological cancers, showed increased expression of HLA-I ("increasing self"), including HLA-C, and mild expression of ligands for NK cell C and L1 C S1 C (e), and KIR2DL2/S2 C and L3 C (f) subsets were set in appropriate dotplots.…”

NK Cell Genotype and Phenotype at Diagnosis of Acute Lymphoblastic Leukemia Correlate with Postinduction Residual Disease

“…In addition to KIRs, other NK cell receptors and effector molecules are crucial determinants of antileukemia response(2, 7, 17, 46). A NCR dull phenotype, for example, has been associated with poor leukemia control in adult AML(3, 4), in line with our data showing that MRD was associated with low expression of NKp46.…”

Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell–depleted stem cell transplantation

“…[1][2][3] The potential for NK cells to mediate antitumor effects has been of particular interest in allogeneic hematopoietic stem cell transplantation (HSCT) (reviewed in Foley et al, 4 Leung, 5 and Locatelli et al 6 ), fueled by animal studies demonstrating that NK cells can facilitate engraftment and augment graft-versus-tumor effects without mediating graft-versus-host disease (GVHD). [7][8][9] Current models hold that this results from differential expression of ligands for NKactivating receptors on malignant cells and hematopoietic cells vs healthy nonhematopoietic tissues.…”