Human cancer gene therapy with cytokine gene-modified cells

Abstract

Cytokines can impede tumour growth and activate innate and adaptive immune responses, leading to elimination of cancer cells. For many years, it was believed that systemic administration of recombinant cytokines might become a standard treatment of different cancer types. However, due to a high toxicity of therapeutic doses and a low efficacy, even in combination with chemotherapy, this strategy is generally not accepted. On the other hand, cancer gene therapy approaches utilising cells modified with cytokine genes seem to represent a novel promising approach. For the last decade, numerous Phase I and II clinical trials evaluating different therapies based on cytokine gene-modified cells have been carried out. In the early studies, several strategies have been shown to improve clinical outcomes and induce strong antitumour immune responses. Recently, a few prospective, randomised, Phase III clinical trials have been initiated in order to finally determine the efficacy of particular cancer immunogene therapy strategies. This article reviews the present status and perspectives of clinical trials of cancer immunotherapies utilising cytokine gene-modified cells.

Cannabinoid 2 receptor induction by IL-12 and its potential as a therapeutic target for the treatment of anaplastic thyroid carcinoma

“…4,5 Cytokine gene therapy has been extensively used for the treatment of cancer in experimental animal models and clinical trials. 6,7 Among many cytokine-based anticancer therapies, interleukin-12 (IL-12) provides one of the most significant antitumor activities in many experimental animal models. 8 We have previously demonstrated that IL-12 is effective against anaplastic thyroid carcinoma in a mouse model.…”

Islet antigen-pulsed dendritic cells expressing ectopic IL-35Ig protect nonobese diabetic mice from autoimmune diabetes

“…We therefore investigated whether IL-35, ectopically expressed by DCs, could also increase Treg cell populations in the NOD diabetes model. Interestingly, by using cytofluorometric analysis, we found that the islet protection and reduced incidence of diabetes observed in the DC 35 cell-sensitized group positively correlated with an increased percentage of CD39 + CD4 + T cells, as compared with the other groups, in pancreatic lymph nodes on day 21, but not 14 after treatment initiation (Fig. 3F).…”

“…In contrast, the group receiving IGRP-pulsed DC 35 cells remained normoglycemic till the 10th week, with the percentage of diabetes incidence rising not over 25% afterwards. The most relevant difference among groups could be observed from the 14th week, when approximately 65-70% of IGRP-pulsed DC Ig -and vehicle-administered mice were hyperglycemic and only 25% of mice vaccinated with IGRP-pulsed DC 35 cells showed blood glucose levels more than 250 mg/dl (Fig. 3B) (DC 35 /IGRP vs DC Ig /IGRP, p < 0.0357; Fig.…”

“…Ectopic expression of cytokines has been studied in different and numerous experimental models in order to understand the functional roles of these molecules and to verify their potential immunotherapeutic effects in conditions of overexpression [35,36]. The production of IL-35Ig by transfected cells may likely generate a surrounding immunosuppressive microenvironment, possibly conditioning the immunological behavior of IL-35Ig-producing as well as bystander cells.…”

Gene-modified tumor vaccine secreting a designer cytokine Hyper-Interleukin-6 is an effective therapy in mice bearing orthotopic renal cell cancer

“…27 Unfortunately, for clinical use all DC-based vaccines must be individualized for each particular patient, are time-consuming and will probably never become an easily accessible off-the-shelf product, which is Hyper-IL6-secreting tumor vaccine in mice with RCC PJ Wysocki et al not the case with the allogeneic, whole-cell tumor vaccines. [28][29][30] In the clinical setting, there is a lack of effective adjuvant therapies, which would significantly decrease the risk of tumor relapse following nephrectomy. Therefore, in our study we have evaluated the efficacy of RENCA-H6 vaccine in such a setting.…”