The evolution of NK cell immunotherapy for hematologic malignancies: A historical and contemporary perspective

In the early to mid 1980s, chemotherapy and total body irradiation followed by bone marrow transplantation gained popularity as a treatment modality for hematologic malignancies [1,2]. In addition to the role of the donor graft in reconstituting the hematopoietic system following the aplasia caused by high-dose chemotherapy and radiation, immunologic recovery from the donor graft was shown to play an important role in the eradication of residual leukemic cells–the so-called graft-versus-leukemia (GvL) effect. Hercend et al demonstrated in 1986 that natural killer (NK) cells are the first immune subset to recover after T-cell depleted allogeneic bone marrow transplantation and that they mediate GvL independent of T cells [3]. Two decades later, the seminal work by Ruggeri et al showed that in the setting of haploidentical transplant, mismatches between the killer immunoglobulin-like receptors on donor NK cells and their ligands in the recipient potentiate the GvL effect and improve outcomes in patients with acute myeloid leukemia [4]. In this special issue, Hsu et al discuss strategies to optimize NK cell alloreactivity in the setting of stem cell transplantation (SCT) by selecting allogeneic donors with specific KIR types and/or KIR-HLA mismatches.

Given the evidence for the potent antileukemic activity of NK cells in the setting of SCT, there was a growing interest in developing strategies for the ex vivo expansion of NK cells for adoptive cellular therapy. Rosenberg et al laid the foundation for adoptive cellular therapy to treat cancer in the early 1980s, using autologous lymphokine-activated killer cells generated ex vivo by culturing patient-derived peripheral blood lymphocytes with high dose interleukin-2 (IL-2) [5,6]. In these studies, lymphokine-activated killer cells were infused to patients with metastatic cancer followed by systemic administration of high dose IL-2 to support their in vivo expansion and persistence. Despite suboptimal clinical responses and unacceptable toxicities from high dose IL-2, objective regressions were observed in a subset of patients, supporting the application of this approach in cancer. Subsequently, multiple groups explored the use of cell therapy with ex vivo expanded autologous NK cells in patients with hematologic or solid tumors [7,8]. While NK cells were found to be safe, clinical responses were disappointing. This was attributed at least partly to the impaired function of NK cells derived from patients with cancer as well as inhibition of autologous NK cells by self-MHC molecules expressed on tumor cells. Moreover, administration of IL-2 can support expansion of regulatory T cells (T_regs), further suppressing NK cell cytotoxicity [9]. These data led to the exploration of alternative cytokines such as IL-15 to support NK cell expansion/activation and the use of allogeneic NK cells for adoptive immunotherapy. In this special issue, Quintarelli et al discuss the advantages and limitations of the various sources of allogeneic NK cells for adoptive cell therapy.

Traditionally NK cells were classified as innate immune cells with a natural capacity to kill transformed cells, without recall or a memory response [10]. However, the discovery of hapten-specific NK cell memory in a murine model of contact hypersensitivity [11] challenged these long-held beliefs. Moreover, paradigm-shifting experiments in murine models showing enhanced NK recall responses against cytomegalovirus [12] and later in human studies in the setting of SCT [13] blurred the divisive lines between the innate and adaptive immune compartments. Around the same time, Yokoyama et al discovered that murine NK cells exposed to proinflammatory cytokines (IL-12, IL-18, and low dose IL-15) develop robust recall responses that are passed onto daughter cells [14]. Fehniger et al later showed that like murine NK cells, human NK cells preactivated with IL-12, IL-18, and IL-15 have enhanced antileukemia functionality [15]. In this special issue, this group discusses the various forms of NK cell memory and their application for cancer immunotherapy.

Other major breakthroughs in the field of NK cell immunotherapy followed advances in cell engineering and gene editing that have made it possible to modify primary NK cells to optimize their persistence, improve their trafficking to tumor sites, enhance their cytotoxicity and redirect their specificity to tumor cells [16]. Given the rapid progress in the field and the promising preclinical and early clinical results with chimeric antigen receptor engineered NK cells [17,18], many groups are now focusing on developing the next generation of engineered NK cells for the treatment of cancer. In this issue, Guimaraes et al summarize the salient aspects of viral and nonviral methodologies for the engineering of NK cells, while Lee et al further elaborate on strategies for the genetic and epigenetic modification of primary NK cells to enhance their antitumor potency using state of the art technologies, such as CRISPR-Cas9 and transposons.

Finally, advances in the understanding of immunometabolism have led several groups to explore strategies to optimize NK cell metabolic fitness and antitumor activity [19,20]. In this special issue, Borrego et al delve into this important topic and provide the reader with an account of the field as it pertains to the optimization of adoptive NK cell therapy.

In summary, this special issue of Seminars in Hematology highlights the evolution of our understanding of NK cell biology and their role in tumor surveillance, along with the progress achieved in their application for the immunotherapy of cancer in general, and hematologic malignancies in particular. Through the content of this issue, the readers will learn how our view of NK cells has gradually shifted from short-lived members of the innate immune system, with spontaneous activity against tumor cells, to sophisticated immune cells with innate and adaptive features and with the potential for memory formation. The articles featured in this issue also address how these cells can be further fine-tuned using state of the art advances in cell engineering, genetic and epigenetic editing and metabolic reconfiguration to become powerful living drugs against cancer. The advances in the field discussed herein will inform the design of the next generation of NK cellular therapies with the hope of improving the clinical management and outcome of patients with hematologic malignancies in the near future.