Cytokine-induced killer cells (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 Cord blood (umbilical cord blood) is blood that remains in the placenta and in the attached umbilical cord after childbirth. Cord blood is collected because it contains stem cells, which can be used to treat hematopoietic and genetic disorders su ...

mononuclear cells with interferon-gamma (

IFN-γ Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...

), 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 Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

release, causing

lysis Lysis ( ) is the breaking down of the membrane of a cell, often by viral, enzymic, or osmotic (that is, "lytic" ) mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a ''lysate''. In molecular bio ...

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

. However, CIK cells have the ability to recognize infected or even malignant cells in the absence of

antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

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 A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...

. As a special feature, terminally differentiated CD3+CD56+ CIK cells possess the capacity for both MHC-restricted and MHC-unrestricted anti-tumor

cytotoxicity Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating cells ...

. These properties, inter alia, rendered CIK cells attractive as a potential therapy for

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

and

viral infections A viral disease (or viral infection) occurs when an organism's body is invaded by pathogenic viruses, and infectious virus particles (virions) attach to and enter susceptible cells. Structural Characteristics Basic structural characteristics, s ...

. A new subclass of NK cells have been created both in vitro and in vivo. These NK cells referred to as cytokine induced memory-like natural killer cells are induced using cytokines, most commonly a mix of IL-12, IL-15, and IL-18. These NK cells are activated by these cytokines to stimulate an infection and induce an adaptive immune response. If cocultured with target cells such as tumor targets, these NK cells have memory-like abilities and are more adapt and effective at mounting a defense.

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 Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...

. Others propose to classify CIK cells as subset of

NKT The New Kadampa Tradition – International Kadampa Buddhist Union (NKT—IKBU) is a global Buddhist new religious movement founded by Kelsang Gyatso in England in 1991. In 2003 the words "International Kadampa Buddhist Union" (IKBU) were ad ...

cells.

Mechanism

It has been shown that

lymphocytes A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adap ...

, when exposed to interferon-gamma, anti-CD3 antibody, interleukin-1 and

interleukin 2 Interleukin-2 (IL-2) is an interleukin, a type of cytokine signaling molecule in the immune system. It is a 15.5–16 kDa protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible for ...

, are capable of lysing fresh, non-cultured

cells, both primary and metastatic. CIK cells respond to these

lymphokines Lymphokines are a subset of cytokines that are produced by a type of immune cell known as a lymphocyte. They are protein mediators typically produced by T cells to direct the immune system response by signaling between its cells. Lymphokines have ...

, particularly

IL-2 The Ilyushin Il-2 (Russian language, Russian: Илью́шин Ил-2) is a Ground attack aircraft, ground-attack plane that was produced by the Soviet Union in large numbers during the World War II, Second World War. The word ''shturmovík'' (C ...

, by lysing tumor cells that were already known to be resistant to

NK cell Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...

or LAK cell activity.

Peripheral blood mononuclear cell A peripheral blood mononuclear cell (PBMC) is any peripheral blood cell having a round nucleus. These cells consist of lymphocytes (T cells, B cells, NK cells) and monocytes, whereas erythrocytes and platelets have no nuclei, and granulocytes (neu ...

s or

mononuclear cells are extracted from either

peripheral blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the c ...

or cord blood, e.g. by simple

blood draw In medicine, venipuncture or venepuncture is the process of obtaining intravenous access for the purpose of venous blood sampling (also called ''phlebotomy'') or intravenous therapy. In healthcare, this procedure is performed by medical labor ...

. Extracted cells are ex-vivo exposed to

interferon-gamma Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...

, anti-CD3 antibody,

interleukin-1 The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults. Discovery Discovery of these cytokines began with studies on t ...

and

interleukin-2 Interleukin-2 (IL-2) is an interleukin, a type of cytokine signaling molecule in the immune system. It is a 15.5–16 kDa protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible for ...

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 Autotransplantation is the transplantation of organs, tissues, or even particular proteins from one part of the body to another in the same person ('' auto-'' meaning "self" in Greek). The autologous tissue (also called autogenous, autogene ...

settings or to different recipients in

allogeneic Allotransplant (''allo-'' meaning "other" in Ancient Greek, Greek) is the Organ transplant, transplantation of cell (biology), cells, Biological tissue, tissues, or Organ (anatomy), organs to a recipient from a genetically non-identical donor of ...

settings. Furthermore, it has been shown that CIK cells have a relevant expression of FcγRIIIa (CD16a), which can be exploited in combination with clinical-grade mAbs to redirect their activity in an antigen-specific manner. Indeed, the engagement of CD16a on CD3+CD56+ cells led to a potent antibody-dependent cell–mediated cytotoxicity (ADCC) both in vitro and in vivo against ovarian cancer.,. Recently, it has been demonstrated the efficacy of a combined approach (CIK + Cetuximab) against triple negative breast cancer (TNBC), an aggressive tumor that still requires therapeutic options. Different primitive and metastatic TNBC cancer mouse models were established in mice, and the treatment CIK cells plus cetuximab significantly restrained primitive tumor growth in mice, either in patient-derived tumor xenografts or MDA-MB-231 cell line models. Moreover, this approach almost completely abolished metastasis spreading and dramatically improved survival. The antigen-specific mAb favored tumor and metastasis tissue infiltration by CIK cells, and led to an enrichment of the CD16a+ subset. Data highlight the potentiality of this novel immunotherapy strategy where a nonspecific cytotoxic cell population can be converted into tumor-specific effectors with clinical-grade antibodies, thus providing not only a therapeutic option for TNBC but also a valid alternative to more complex approaches based on chimeric antigen receptor-engineered cells.

Function

The mechanism of CIK cells is distinctive from that of

natural killer cells Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...

or LAK cells because they can lyse cells that

and LAK cells cannot. CIK cells have, as a key feature, a double

T-cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...

and

-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 NKG2D is an activating receptor (transmembrane protein) belonging to the NKG2 family of C-type lectin, C-type lectin-like receptors. NKG2D is encoded by ''KLRK1'' (killer cell lectin like receptor K1) gene which is located in the NK-gene complex ...

, DNAM-1 and NKp30. These receptors and surface markers confer the capability of acting against cells that do not display the

major histocompatibility complex The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are calle ...

, as has been shown by the ability to cause

in non-immunogenic,

and syngeneic tumors. Particularly solid and hematologic tumor cells tend to overexpress

ligands, making them a sought target of CIK cell-mediated

cytolysis Cytolysis, or osmotic lysis, occurs when a cell bursts due to an osmotic imbalance that has caused excess water to diffuse into the cell. Water can enter the cell by diffusion through the cell membrane or through selective membrane channels ...

. Recognition is specific to tumor and virus infected cells as CIK cells do not display activity against healthy cells. Immunomodulatory

Tregs The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosup ...

were shown to inhibit CIK cell function.

Cancer Treatment

CIK cells, along with the administration of

have been experimentally used to treat

in mice and humans with low

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...

Clinical trials

In a large number of phase I and phase II

studies Study or studies may refer to: General * Education **Higher education * Clinical trial * Experiment * Observational study * Research * Study skills, abilities and approaches applied to learning Other * Study (art), a drawing or series of drawin ...

, autologous and allogeneic CIK cells displayed a high cytotoxic potential against a broad range of varying tumor entities, whereas

side effects In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

were only minor. In many cases, CIK cell treatment led to

complete remission Remission is either the reduction or disappearance of the signs and symptoms of a disease. The term may also be used to refer to the period during which this reduction occurs. A remission may be considered a partial remission or a complete remissio ...

s of tumor burden, prolonged survival durations and improved

quality of life Quality of life (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...

, even in advanced disease stages. Currently, the utilization of CIK cell treatment is restricted to

clinical studies Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

, but this therapeutic approach might also benefit patients as

first-line treatment A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis. As a rule, each therapy has indications and contraindications. There are many different ...

modality in the future.

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

, researchers succeeded in the

transfection Transfection is the process of deliberately introducing naked or purified nucleic acids into eukaryotic cells. It may also refer to other methods and cell types, although other terms are often preferred: "transformation" is typically used to desc ...

of cells ex-vivo with

genes In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

, e.g.

. Gene-modified CIK cells showed an increased proliferation rate and enhanced

. 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

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 receptor In biology, chimeric antigen receptors (CARs)—also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors—are receptor proteins that have been engineered to give T cells the new ability to target a specific ...

s 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 A bispecific monoclonal antibody (BsMAb, BsAb) is an artificial protein that can simultaneously bind to two different types of antigen or two different epitopes on the same antigen. Naturally occurring antibodies typically only target one antigen. ...

, 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.

References

[Rosato Antonio, Sommaggio Roberta (Aug 2017). "Cytokines for the induction of antitumor effectors: The paradigm of Cytokine-Induced Killer (CIK) cells". Cytokine Growth Factor Rev. 36: 99–105. doi:10.1016/j.cytogfr.2017.06.003. .]

External links

Cytokine-Induced Killer Cells
at the US National Library of Medicine

Medical Subject Headings Medical Subject Headings (MeSH) is a comprehensive controlled vocabulary for the purpose of indexing journal articles and books in the life sciences. It serves as a thesaurus that facilitates searching. Created and updated by the United States N ...

(MeSH)
International registry on CIK cells (IRCC)

Definition of CIK cells
by the National Cancer Institute {{Lymphocytes Immune system Lymphocytes Cancer treatments