The IL-2 cytokine family in cancer immunotherapy

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.

Cellular therapy: Adoptive immunotherapy with expanded natural killer cells.

https://www.jidonline.org/article/S0022-202X(15)36508-8/pdf

Imiquimod Inhibits Melanoma Development by Promoting pDC Cytotoxic Functions and Impeding Tumor Vascularization

Irradiation of breast cancer cells enhances CXCL16 ligand expression and induces the migration of natural killer cells expressing the CXCR6 receptor

Natural killer (NK) cells can be expanded upon activation by proliferative cytokines (such as IL-2 and IL-15). The NK cell expansion can be greatly enhanced by proteins from feeder cells such as tumor cell lines or PBMCs. Therefore, coculture systems of irradiated feeder cells and NK cells in media containing IL-2 and IL-15 have been developed to generate large numbers of NK cells, although NK cell expansion protocol using anti-CD3 antibody (OKT-3) without feeder cells has also been developed. Commonly used feeder cell lines are RPMI8866, Epstein-Barr lymphoblastoid cell line (EBV-LCL), and K562. Stimulation with NK-sensitive K562 cells is known to augment NK cell proliferation to IL-2, IL-15, and IL-21 in combination.Recently, remarkable NK cell-expansion rates are achieved when genetically engineered (GE) feeder cells are used. Dr. Dario Campana's group found that membrane-bound IL-15 and 4-1BBL, coexpressed by K562 cells, acted synergistically to augment K562-specific NK stimulatory capacity, resulting in vigorous expansion of peripheral blood CD56(+) CD3(-) NK cells without concomitant growth of T lymphocytes. Here, we describe an in vitro expansion method of human NK cells among PBMCs by coculturing with GE_K562 cells.

Expansion of NK Cells Using Genetically Engineered K562 Feeder Cells.

Background/aim Interleukin-21(IL-21) stimulates cytotoxicity and interferon-γ (IFN-γ) production in natural killer (NK) cells. However, little has been reported on the stimulatory effect of IL-21 on ex vivo expanded NK cells. In this study, we examined the cytotoxicity and IFN-γ production of ex vivo expanded, IL-21-stimulated NK cells against trastuzumab-coated breast cancer cells. Materials and methods To expand NK cells, peripheral blood mononuclear cells (PBMCs) were isolated and co-cultured with irradiated K562-mb15-41BBL cells in the presence of IL-2 and IL-15 for 3 weeks. After a 4-day stimulation with IL-21, NK cell cytotoxicity and IFN-γ production were measured. Results NK cells were expanded up to median of 911-fold and represented approximately 94.93% of expanded cells after 21 days. Cytotoxicity of the expanded NK cells against the MCF-7, SKBR3, and T47D cell lines was significantly increased following 4-day stimulation with IL-21. However, antibody-dependent cellular cytotoxicity mediated by trastruzumab was significantly increased only in the SKBR3 cell line, which highly expresses the HER2/neu antigen. IL-21 pre-treatment also increased IFN-γ production in the expanded NK cells in response to the trastuzumab-coated breast cancer cells. Conclusion IL-21 significantly enhances the cytolytic activity and IFN-γ production of ex vivo expanded NK cells in response to trastuzumab-coated breast cancer cells.

Interleukin-21 increases direct cytotoxicity and IFN-γ production of ex vivo expanded NK cells towards breast cancer cells

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Interleukin-21 increases direct cytotoxicity and IFN-γ production of ex vivo expanded NK cells towards breast cancer cells