Arming Immune Cells for Battle: A Brief Journey through the Advancements of T and NK Cell Immunotherapy

Abstract

The promising development of adoptive immunotherapy over the last four decades has revealed numerous therapeutic approaches in which dedicated immune cells are modified and administered to eliminate malignant cells. Starting in the early 1980s, lymphokine activated killer (LAK) cells were the first ex vivo generated NK cell-enriched products utilized for adoptive immunotherapy. Over the past decades, various immunotherapies have been developed, including cytokine-induced killer (CIK) cells, as a peripheral blood mononuclear cells (PBMCs)-based therapeutic product, the adoptive transfer of specific T and NK cell products, and the NK cell line NK-92. In addition to allogeneic NK cells, NK-92 cell products represent a possible “off-the-shelf” therapeutic concept. Recent approaches have successfully enhanced the specificity and cytotoxicity of T, NK, CIK or NK-92 cells towards tumor-specific or associated target antigens generated by genetic engineering of the immune cells, e.g., to express a chimeric antigen receptor (CAR). Here, we will look into the history and recent developments of T and NK cell-based immunotherapy.

The Dual Role of Innate Lymphoid and Natural Killer Cells in Cancer. from Phenotype to Single-Cell Transcriptomics, Functions and Clinical Uses

“…We will focus on pros and cons related to three major items: (a) the source of NK cells (from progenitors or from already-differentiated cells); (b) the use of autologous vs. allogeneic NK cells; and (c) the use of naïve vs. activated, engineered or monoclonal-antibody-associated NK cells. As recently reviewed by Wendel et al [2], Riendl et al [149] and Gauthier et al [150], clinical immunotherapy trials involving NK cells are ongoing in both hematological malignancies (acute and chronic leukemia, aggressive and indolent lymphomas as well as myelomas) and (to a lower extent) in solid cancers, in the pancreas, the prostate, the ovary, the breast, the brain, the lung, the liver and the digestive tube.…”

“…At the present time, a very large majority of clinical trials involving NK cells designed for cancer patients are using mature cells collected from the PB of healthy donors; these cells become naïve or activated after being exposed to cytokines ex vivo or after infusion. Only a minority of trials are using UCB-or PB-derived CD34 + progenitors expanded ex vivo before being reinfused, cytokine-induced killer (CIK) cells or engineered CAR-NK cells [2,149], which will be discussed below.…”

“…To overcome these limits, IL-15 or the IL-15 superagonist ALT-803 have been used more recently to activate NK cells and induce their proliferation in clinical trials [169]. Further preclinical and clinical strategies to activate and expand NK cells by means of IL-12, IL-18, IL-21 or cell feeders expressing one or more of these cytokines in addition to IL-2 have been or are currently investigated in a variety of clinical trials worldwide [2].…”

“…In spite of these potential advantages, currently ongoing CAR-NK cell therapy trials (in most cases involving CD19 as a target in NHL and CD123 as a target in AML) are significantly less frequent compared to ongoing CAR-T cell trials. However, this scenario might change in the near future [2].…”

“…Cancers 2021, 13, 5042 2 of 32 Evolutionary studies suggest that the innate immune system is a very old defense strategy, as it is the dominant one in plants, fungi and insects. It can overcome many threats, but in vertebrates the adaptive section of the immune orchestra is crucial to reach acquired immunity [2].…”