CIK cells – current status, clinical perspectives and future prospects – the good news

Keywords::

• adoptive immunotherapy
• cancer
• cytokine-induced killer
• solid tumors

There is an ongoing explosion of knowledge in pursuing the adoptive immunotherapy of cancer to offer an alternative and/or supplementary approach for the treatment of human cancer refractory to conventional therapies. Important issues for developing effective adoptive immunotherapy strategies include the generation of sufficient functional immune effectors, the efficient recognition and lysis of tumor targets by the effectors and overcoming the restriction to specific human leukocyte antigen (HLA) haplotypes.

Cytokine-induced killer (CIK) cells are cytotoxic immune effector T cells that are readily expandable and express in addition to the T cell marker CD3, markers typically associated with natural killer (NK) cells such as CD56 and NKG2D [1]. CIK cells are generated by the in vitro culture of peripheral blood lymphocytes with IFN-γ, IL-2 and anti-CD3. Under stimulation by cytokines, it was feasible to expand CIK cells from peripheral blood of healthy donors and cancer patients who had undergone prior chemotherapy [1]. Following cell expansion, activation occurs, resulting in cytolytic effector CIK cells that recognize targets through NKG2D, an activating receptor expressed on all NK cells and serves as a T cell co-stimulatory molecule. This provides a clinically appealing property of CIK cells since CIK cell-mediated cytotoxicity is HLA-unrestricted and T cell receptor-independent, with target killing occurring through NKG2D-mediated recognition. Similar ex vivo protocols have been adopted to expand CIK cells from peripheral blood of patients under good manufacturing practice (GMP) conditions for clinical studies. These trials have reported efficacy with well-tolerated toxicities in the treatment of patients with metastatic diseases, lymphoma and acute leukemia. For example, a recent Phase I dose-escalation trial by Negrin's group with allogeneic CIK cell infusions in patients with relapsed hematologic malignancies reached the planned maximum cell dose of 1 × 10⁸ CD3⁺ cells/kg as the maximum tolerated dose with low incidence of graft-versus-host disease (GVHD) paralleled to that reported in preclinical models [2] and provides further rationale of the clinical use of CIK cells.

The accompanying two publications critically review and summarize the latest and the most important clinical immunotherapeutic strategies with CIK cells aiming at providing a multidisciplinary update for basic and clinical researchers about the broad scope of cell therapy with CIK cells. The review by Sangiolo entitled ‘Cytokine-induced killer (CIK) cells as feasible and effective adoptive immunotherapy for the treatment of solid tumors’ highlights the biological characteristics of CIK cells, focusing on their potential usefulness for clinical applications [3]. Published preclinical studies and reports of clinical trials with CIK cells were also discussed and summarized. Recently, many innovative therapeutic strategies aimed at broadening the application of CIK cells have been reported. These are CIK-centered therapies and in combination with other treatment modalities. One such treatment strategy employed CIK cells in combination with CD3xCA125 or CD3xHer2 bi-specific antibodies to render CIK-resistant primary ovarian carcinoma cells susceptible to CIK-mediated lysis [4]. It is in this context that the second review by Schmidt-Wolf entitled ‘New adoptive immunotherapy strategies for solid tumors with CIK cells’ provides an overview of the recent exciting advances in adoptive cancer immunotherapy strategies using CIK cells [5]. Additionally, this review also summarize the many recent innovative approaches of combining CIK cells with conventional and well-established treatment modalities for human cancer to synergize the treatment outcomes of CIK cells employed in isolation. Reading of these two reviews will undoubtedly offer a balanced view of the current status of CIK cells for the adoptive immunotherapy of human cancers.

Many of the attributes and rationales for the clinical use of CIK cells have been developed over the past 20 years by the collective effort of many investigators in the field. In preclinical studies, CIK cells have shown potent activity against an array of tumor cell lines, with a markedly reduced capability to induce GVHD in murine models, bioluminescent imaging has demonstrated the ability of CIK cells to traffic to tumor sites where they persisted to eradicate tumor cells. CIK cells generated from patients with acute myelogenous leukemia (AML) have demonstrated cytotoxic activity against both autologous and allogeneic leukemic blasts. In addition, CIK cells show minimal or no cytotoxicity against normal tissues including CD34 stem cells and do not suppress marrow engraftment in vivo, and induce minimal GVHD in allogeneic models. Compared with CD3–CD56 lymphokine-activated killer cells, CIK cells have been demonstrated to generate greater cytotoxicity against multidrug-resistant tumor cell lines and are more readily expandable.

Further advances in our understanding of the molecular interactions between CIK cells and the tumor targets would certainly provide the basis for designing more efficient immunotherapy strategies. In this context, we have demonstrated that the majority of the highly expressed genes of the various CD3⁺CD56⁺ CIK effectors were regulated in concordance with, and were consistent with, a Th1 and Tc1 polarization. Genes related to protein synthesis were highly expressed in CIK cells, and on stimulation by leukemic targets, genes related to signaling, immune responses and transcription were up-regulated. More importantly, and corroborated with their cytolytic activities, the NK receptors genes, NKG2C and NKG2E, together with perforin, were up-regulated exclusively in CIK cells that were cytolytic to susceptible AML targets. In comparison, transforming growth factor β1, a cytokine with immune inhibitory function, was exclusively up-regulated in CIK cells that were exposed to resistant acute lymphoblastic leukemic (ALL) targets [6].

In conclusion, CIK cells are endowed with a MHC-independent tumor killing capacity against both solid and hematologic malignancies. As an immunotherapeutic modality, infusion of CIK cells is most likely to show efficacy in a relatively low tumor burden stage or in an adjuvant setting, rather than in high tumor burden diseases. The relatively robust and simple cell culture procedures to expand CIK cells have enabled this approach of adoptive cellular immunotherapy for cancer to be increasingly studied across the world. We have recently demonstrated that following bulk culture in vitro, the effector CIK cell population generated is heterogeneous with the sorted CD3⁺CD56⁺ cell fraction gave the best cytolytic activities against both autologous and allogeneic susceptible tumor targets compared with the other cell subsets [7]. With these rationales, it would justify to perform large-scale randomized controlled trials to fully evaluate the efficacy of the different CIK cell subsets with or without the combination of other treatment modalities. Furthermore, a recent new initiative has been launched by Schmidt-Wolf with the aim to establish an international registry to collect and eventually standardize the clinical data and treatment of patients with cancer using CIK cells. Clinical trials set in a standardized reporting system will undoubtedly accelerate discoveries and eventually improve treatment with CIK cells to benefit patients [8].

Declaration of interest

The author states no conflict of interest and has received no payment in preparation of this manuscript.