Natural Killer Cells for Therapy of Leukemia

Abstract

Clinical application of natural killer (NK) cells against leukemia is an area of intense investigation. In human leukocyte antigen-mismatched allogeneic hematopoietic stem cell transplantations (HSCT), alloreactive NK cells exert powerful anti-leukemic activity in preventing relapse in the absence of graft-versus-host disease, particularly in acute myeloid leukemia patients. Adoptive transfer of donor NK cells post-HSCT or in non-transplant scenarios may be superior to the currently widely used unmanipulated donor lymphocyte infusion. This concept could be further improved through transfusion of activated NK cells. Significant progress has been made in good manufacturing practice (GMP)-compliant large-scale production of stimulated effectors. However, inherent limitations remain. These include differing yields and compositions of the end-product due to donor variability and inefficient means for cryopreservation. Moreover, the impact of the various novel activation strategies on NK cell biology and in vivo behavior are barely understood. In contrast, reproduction of the third-party NK-92 drug from a cryostored GMP-compliant master cell bank is straightforward and efficient. Safety for the application of this highly cytotoxic cell line was demonstrated in first clinical trials. This novel ‘off-the-shelf' product could become a treatment option for a broad patient population. For specific tumor targeting chimeric-antigen-receptor-engineered NK-92 cells have been designed.

CAR-Expressing Natural Killer Cells for Cancer Retargeting

“…Due to their shorter life span in comparison to T cells, CD33-directed CAR-modified NK-92 cells (second-generation CAR, CD28-CD3ζ) were designed and exerted potent cytotoxic activity against target cells in chromium-51-release assays [43]. Efficacy and safety data of allogeneic or haploidentical NK cell transplantations including NK-92 have been obtained from several clinical trials [reviewed in 44, 45]. However, a clinical phase I/II trial was enrolled in 2016 testing the safety and toxicity of CD33-directed NK-92 cell infusions (CD33-CD3ζ-CD28-4-1BB) in patients whose leukaemic disease relapsed (after stem cell transplantation and chemotherapy) or appeared refractory to treatment (NCT02944162; https://clinicaltrials.gov; Table 1).…”

Immunological and Translational Aspects of NK Cell-Based Antitumor Immunotherapies

“…NK cells not only control tumor progression but are also engaged in reciprocal interactions with dendritic cells (DCs), macrophages, T cells, and endothelial cells (2). Clinical application of NK cells is an area of intense investigation not only in oncology, especially in hematological malignancies, including leukemia and lymphoma, but also in solid tumors such as ovarian cancer, sarcoma, hepatocellular carcinoma, glioblastoma, and many other types (3–9). Adoptive transfer of autologous or allogeneic NK cells might be superior to the currently widely used donor lymphocyte infusion, which predominantly contain T lymphocytes, due to the fact that NK cells provide the first line of defense and generally mediate less graft-versus-host disease (GvHD) than T cells (10, 11).…”

Challenges of NK cell-based immunotherapy in the new era

“…An undergoing study have moved forward to phase-II clinical trials for the assessment of the effects of radiochemotherapy with NK cells on patients with non-small-cell lung cancer [89]. Several clinical trials combining NK cells and chemotherapy for solid tumor treatment are underway [61,90,91]. Chemotherapy has been shown to promote the sensitivity of tumor cells to NK cells and deplete immune cells to make room for infused NK cells [92,93].…”

“…Bi-or tri-specific killer engagers that can enhance the targeting of NK cells to tumor cells and augment the cytotoxicity of NK cells have been intensively studied [98,99]. However, the outcomes of these combination therapies are diverse, and the role of these accelerants in combination with NK-cell therapy remains to be validated clinically [61,78,90,91]. These phenomena are probably caused by poor persistency and proliferation of NK cells in vivo.…”