Pioneering Adoptive Immunotherapy with Natural Killer Cells

Natural killer (NK) cells hold tremendous potential for hematotherapy with well-documented application(s) in therapy of hematologic malignancies. They also hold a largely untapped potential in the therapy of solid tumors, viral infections, and viral-associated diseases. The NK cells were first described and named based on their ability to recognize malignant leukemia cells without prior sensitization, in what appeared as a “natural” and human leukocyte antigens (HLA)-independent manner [1,2]. The early wave of enthusiasm in NK cells was not fulfilled in the clinic. Clinical trials were using interleukin-2 (IL-2) and adoptive immunotherapy with activated NK cells and effector T cells (lymphokine-activated killer cells). Objective responses were seen in immune-sensitive tumors such as renal cell cancer and melanoma, but no benefit in overall survival was seen [3]. The lesson learned was that we are able to boost NK cell activation using IL-2, but this did not significantly control the malignant cells [4]. As we know today, this may be due to IL-2 also activating regulatory T cells (T regs), which are recognized by high level of CD25, receptor for IL-2 [5].

The proof for potential of NK cells was made possible by the discovery of the mode of recognition of the target cells by NK cells. NK cells learn to recognize the self HLA, and that endows them with a license to kill target cells based on their lack or loss of given HLA. The other side of the equation is the activation of NK cells, mediated by activating receptors. Some of the activating factors are stress- or transformation-induced molecules such as ligands for NKG2D. One of the most convincing proofs of the NK cell potential was provided by retrospective analysis of results of haploidentical hematopoietic stem cell transplants [6]. All the recipient–donor pairs were HLA mismatched on one haplotype; some of the recipient–donor pairs configurations were such that the donor NK cells would see “lack of self” HLA on the leukemia cells. The patients who were missing HLA considered “self” by donor NK cells had significantly lower risk of leukemia relapse. The difference was significant enough to boost worldwide efforts to exploit NK cell's potential further.

The challenges and opportunities for NK cell application include the difficulty obtaining large doses of NK cells for infusion. The activity in clearance of disease depends on sufficient numbers of NK cells at the right place and time. Some of the attempts to overcome this limitation include generation of NK cells in vitro from hematopoietic stem cells such as those present in cord blood. As well, NK cells can be generated from embryonic stem cells or induced pluripotent stem cells. The goal is to obtain large quantities of NK cells as an “off the shelf” cellular immunotherapy product.

Pioneers such as Dr. Jeffrey Miller have fostered an outstanding training and developmental environment, sparking a whole wave of clinical NK cell researchers venturing into the area of adoptive immunotherapy. Dr. Miller has been an excellent mentor, open for exploring new avenues and committed to helping patients with otherwise incurable disease, according to the motto of C. Walton Lillehei “What mankind can dream research and technology can achieve.”

As I embark on a career of physician–scientist, as a mentor I would like to encourage pursuing original ideas and support talented people who have the enthusiasm and persistence required to thrive in this beautiful and fascinating field.

The little-known truth about NK cells is that they are distinct from T cells, yet they share many similarities and parallels with them. From the days of discovery to the era of burst of immunotherapy as we see today, NK cells remain in the shadow of T cells. Some of their unique advantages such as no requirement for major histocompatibility complex (MHC) restriction and relative ease of in vitro generation from multipotent precursors hold promise for the future of adoptive immunotherapy.