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Cytokine-induced killer cell

Abstract

Cytokine-induced killer cells or CIK cells are a group of immune effector cells featuring a mixed T- and natural killer (NK) cell-like phenotype. They are generated by ex vivo incubation of human peripheral blood mononuclear cells (PBMC) or cord blood mononuclear cells with interferon-gamma (IFN-γ), anti-CD3 antibody, recombinant human interleukin (IL-) 1 and recombinant human interleukin (IL)-2.

Typically, immune cells detect major histocompatibility complex (MHC) presented on infected cell surfaces, triggering cytokine release, causing lysis or apoptosis. However, CIK cells have the ability to recognize infected or even malignant cells in the absence of antibodies and MHC, allowing for a fast and unbiased immune reaction. This is of particular importance as harmful cells that are missing MHC markers cannot be tracked and attacked by other immune cells, such as T-lymphocytes. As a special feature, terminally differentiated CD3+CD56+ CIK cells possess the capacity for both MHC-restricted and MHC-unrestricted anti-tumor cytotoxicity.

These properties, inter alia, rendered CIK cells attractive as a potential therapy for cancer and viral infections.

Nomenclature

They were given the name “cytokine-induced killer” because cultivation with certain cytokines is mandatory for the maturation into terminally differentiated CIK cells. Several sources also call them natural killer cell-like T cells due to their close relationship to NK cells. Others propose to classify CIK cells as subset of NKT cells.

Mechanism

It has been shown that lymphocytes, when exposed to interferon-gamma, anti-CD3 antibody, interleukin-1 and interleukin 2, are capable of lysing fresh, non-cultured cancer cells, both primary and metastatic. CIK cells respond to these lymphokines, particularly IL-2, by lysing tumor cells that were already known to be resistant to NK cell or LAK cell activity.

Peripheral blood mononuclear cells or cord blood mononuclear cells are extracted from either peripheral blood or cord blood, e.g. by simple blood draw. Extracted cells are ex-vivo exposed to interferon-gamma, anti-CD3 antibody, interleukin-1 and interleukin-2 in a time-sensitive schedule. These cytokines strongly stimulate the proliferation and maturation into CIK cells.

After completed maturation CIK cells are transfused to the donor in autologous settings or to different recipients in allogeneic settings.

Function

The mechanism of CIK cells is distinctive from that of natural killer cells or LAK cells because they can lyse cells that NK cells and LAK cells cannot.

CIK cells have, as a key feature, a double T-cell and NK cell-like phenotype. This unique combination of T-cell and NK-cell capabilities exerts a potent and widely MHC-unrestricted anti-tumor cytotoxicity against a broad range of cancer cells.

Up to now the exact mechanisms of tumor recognition and targeted cytotoxicity of CIK cells is not fully understood. Besides recognition via TCR/CD3, NK-cell-like tumor recognition is mediated by cell-cell contact-dependent NKG2D, DNAM-1 and NKp30. These receptors and surface markers confer the capability of acting against cells that do not display the major histocompatibility complex, as has been shown by the ability to cause lysis in non-immunogenic, allogeneic and syngeneic tumors. Particularly solid and hematologic tumor cells tend to overexpress NKG2D ligands, making them a sought target of CIK cell-mediated cytolysis. Recognition is specific to tumor and virus infected cells as CIK cells do not display activity against healthy cells.

Immunomodulatory Tregs were shown to inhibit CIK cell function.

Cancer Treatment

CIK cells, along with the administration of IL-2 have been experimentally used to treat cancer in mice and humans with low toxicity.

Cancer Treatment | Clinical trials

In a large number of phase I and phase II studies, autologous and allogeneic CIK cells displayed a high cytotoxic potential against a broad range of varying tumor entities, whereas side effects were only minor. In many cases, CIK cell treatment led to complete remissions of tumor burden, prolonged survival durations and improved quality of life, even in advanced disease stages.

Currently, the utilization of CIK cell treatment is restricted to clinical studies, but this therapeutic approach might also benefit patients as first-line treatment modality in the future.

Cancer Treatment | International registry on CIK cells (IRCC)

The international registry on CIK cells (IRCC) was founded in 2011 as an independent organization, dedicated to collect data about clinical trials utilizing CIK cells and subsequent analysis to determine the latest state of clinical CIK cell research. A particular focus is thereby the evaluation of CIK cell efficacy in clinical trials and side effects.

Future trends

In studies, researchers succeeded in the transfection of cells ex-vivo with cytokine-genes, e.g. IL-2. Gene-modified CIK cells showed an increased proliferation rate and enhanced toxicity. Gene-transfected CIK cells were first applied in 1999 for the treatment of ten patients in metastatic state of disease.

Evidence is growing that the interaction with dendritic cells (DC) or rather vaccinated DCs further improves the anti-tumor efficacy of CIK cells and joint cultivation additionally reduces the number of Tregs within the CIK cell culture, resulting in enhanced expansion and frequency of CD3+CD56+ cells in the amplified cell population.

In-vitro studies revealed that CIK cells, redirected by chimeric antigen receptors with an antibody-defined specificity for different tumor antigens, showed an improved selectivity and activation in targeting antigen-presenting tumor cells.

In-vitro and in-vivo activity of CIK cells in conjunction with bispecific antibodies, cross-linking cytotoxic effector cells with malignant targets, was enhanced compared with CIK cells alone.

History

CIK cells were first described by Ingo G.H. Schmidt-Wolf in 1991, who also performed the first clinical trial with CIK cells in the treatment of cancer patients in 1999.