The process of antibody-dependent cell-mediated cytotoxicity (ADCC) makes use of the innate immune cells providing antitumor cytotoxicity activated by antibodies linked to target cells. Natural killer (NK) cells are a small set of lymphocytes, but are considered the most important cells among those able to induce ADCC. They provoke innate immune responses and harmonise spontaneous cytotoxicity towards tumor and virus-infected cells. They are able to swiftly produce biochemical signals and cytokines so as to stimulate subsequent adaptive immune responses. Immunotherapeutics that target NK cells, augmenting their immune response, can cause the antitumor dynamics of the antibodies to be improved. The recent developments in the field of NK cell immunotherapy and genotypic factors which might affect patient responses to antibody-dependent immunotherapies are the main subject of this review, with a particular focus on the manipulations and strategies used to augment ADCC. In the next years combined treatment with monoclonal antibodies (mAbs) and immunomodulatory drugs will be an important part in antitumor therapy. The main challenge remains the difficulty in distinguishing in the clinical setting, between the target effect that many mAbs exert against specific cell membrane receptors and the ADCC effect that they too also can induce. Drugs able to activate NK cells, that are major actors in mAb-mediated ADCC, will improve the ADCC effect against tumors.
Purpose: The multikinase inhibitor sorafenib displays antitumor activity in preclinical models of osteosarcoma. However, in sorafenib-treated patients with metastatic-relapsed osteosarcoma, disease stabilization and tumor shrinkage were short-lived and drug resistance occurred.
Cytokine-induced killer (CIK) cells are a heterogeneous subset of ex-vivo expanded T lymphocytes which present a mixed T-NK phenotype and are endowed with a MHC-unrestricted antitumor activity. The main functional properties of CIK cells may address some of the main limitations that are currently preventing the successful clinical translation of adoptive immunotherapy strategies. Clinically adequate quantities of immune effectors, sufficient for multiple adoptive infusions, may be obtained based on their relatively easy and inexpensive ex-vivo expansion starting from peripheral blood mononuclear cells. The MHC-unrestricted tumor-killing is mainly based on the interaction between NKG2D molecules on CIK cells and MIC A/B or ULBPs molecules on tumor cells; it has been proved effective against several solid and hematological malignancies and does not require any HLA-restriction increasing the number of patients that might potentially benefit from such approach. Finally, CIK cells present a reduced alloreactivity across HLA-barriers with important clinical implications for their potential use as alternative to conventional Donor Lymphocyte Infusions after allogeneic hemopoietic cell transplant with a reduced risk of GVHD. In the present report we review the main functional characteristics of CIK cells discussing recent findings and future perspectives to improve their antitumor activity and potential clinical applications.
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