Cellular therapy: Adoptive immunotherapy with expanded natural killer cells

Abstract

Adoptive immunotherapy with natural killer cells was pioneered 30 years ago in human clinical trials with the development of cytokine‐induced killer cells—unfractionated peripheral blood mononuclear cell (PBMC) populations activated overnight with IL‐2. Higher doses were subsequently made possible through the advent of steady‐state apheresis, allowing the collection of PBMC numbers equivalent to an entire adult blood volume, and increased purity made feasible through magnetic CD3‐depletion and/or CD56‐selection methods. Still, these approaches rarely achieved clinical dosing above a single infusion of 108 NK cells/kg, except with substantial donor‐recipient size mismatch (eg, parents donating cells to children). To address this shortcoming, leukemia cell lines with NK cell‐like function or ex vivo expansion approaches centered on the homeostatic cytokine IL‐15 were developed. Here, we describe the development of an ex vivo expansion system based on a feeder cell expressing membrane‐bound IL‐21 that enables log‐phase growth of primary NK cells for many weeks without inducing senescence, and describe the biology, correlative science, and translation to clinical trials for patients with leukemia, brain tumors, and solid tumors.

Highly efficient serum-free manipulation of miRNA in human NK cells without loss of viability or phenotypic alterations is accomplished with TransIT-TKO

“…Capable of immune polarization, target cell killing and self-tolerance, NK cells are attractive as tools for immunotherapy. NK cells do not require strict HLA matching, and have not been associated with substantial toxicity or off-target effects and may therefore be applicable as offthe-shelf adoptive cell therapies [22,41,42]. Increasingly, there is interest in engineering NK cells (i.e.…”

“…Approaches are established for expansion, engineering and delivery of NK cells [20][21][22], but strategies to efficiently target miRNA in particular are lacking. Tailoring of the miRNA environment in NK cells may allow control in complex cellular processes to polarize NK cells for inflammation or regulation.…”

Immunotherapies for pediatric cancer: current landscape and future perspectives

“…Additionally, these lymphocytes have anti-viral and antigraft-versus-host disease potential, which makes them an excellent option for adoptive pediatric cancer immunotherapy [110,111]. In allogeneic stem cell and autologous hematopoietic stem cell transplantation (HSCT), NK cells play an essential role in graft versus leukemia.…”

“…NK cells can be isolated from different sources such as peripheral blood of haploidentical, allogeneic, or autologous donors as well as cord blood and induced pluripotent stem cells (iPSC). To achieve sufficient volumes of NK cells for clinical use, ex vivo expansion systems using K562 feeder cells are designed to engage and activate NK cells with membrane bound ligands such as mbIL21-41BBL or mbIL15-41BBL as well as a combination of multiple stimulatory cytokines such as IL-2, IL-12, IL-15, and IL-18 [111]. To avoid using leukemic feeder cells in the culture process, generating small fragments of a manipulated form of K562 feeder cells is an alternative option to effectively engage NK cells and trigger expansion [115].…”

“…Several clinical trials for adult and pediatric patients with leukemia, brain tumors such as medulloblastoma and glioblastoma, sarcomas such as osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and neuroblastoma have been conducted using ex vivo expanded NK cells. Recently, one of us (DAL) extensively reviewed the many clinical trials in which these cells have been used [111]. The safety, efficacy, and tolerability of NK cells in these clinical trials have shown promising results.…”