Genetically engineered recombinant adenovirus expressing interleukin‑2 for hepatocellular carcinoma therapy

Abstract

Regulatory and effector T cells possess immunological cytotoxicity for tumor cells in the tumor microenvironment during tumor progression and are the primary suppressors inhuman cancer therapy. Interleukin‑2 (IL‑2) is an anticancer cytokine, which triggers human innate and adaptive immunity by stimulating T cell propagation and lymphocyte infiltration into tumor sites. IL‑2 has been used successfully for cancer therapy. Recombinant adenovirus expressing IL‑2 (rAd‑IL‑2) injection is a gene therapy agent that may improve prognosis of hepatocellular carcinoma (HCC) patients. In the present study, the ability of IL‑2 to stimulate an immune response and the ability of recombinant adenovirus to inhibit tumor cell growth in HCC was investigated in a HCC tumor model. It was demonstrated that the regulatory and effector cell‑mediated tumor suppression by antitumor cluster of differentiation (CD)4+ and CD8+ T cells stimulated by rAd‑IL‑2 is tumor‑specific. Furthermore, rAd‑IL‑2 significantly stimulated tumor‑specific cytotoxic T lymphocyte responses, increased interferon‑γ release and enhanced antitumor immunity by inducing CD4+ and CD8+ T cell recruitment into the tumor, and additionally induced memory to protect tumor‑bearing mice against tumor challenge. Treatment with rAd‑IL‑2 led to tumor regression and long‑term survival of mice in the 120‑day treatment period. Tumor challenge experiments demonstrated that rAd‑IL‑2 induced memory, protecting against reinfection. In conclusion, rAd‑IL‑2 may promote tumor‑associated effector and regulatory T cell expansion and may be a potential therapeutic agent for clinical immunotherapy application in the treatment of cancer.

Oncolytic Adenovirus—A Nova for Gene-Targeted Oncolytic Viral Therapy in HCC

“…Furthermore, an increasing amount of research has reported that oncolytic adenoviruses are capable of infecting and expressing exogenous functional genes with no target cells. The functional/effector genes can be classified in four categories by their functions: (1) Tumor-suppressor gene (51, 52); (2) Cytotoxic gene; (3) Immune-modulating gene (53); (4) Tumor-antigens (54). The following is the detailed introduction of genes carried by oncolytic adenoviral vectors for HCC treatment.…”

“…In addition to IL-24 and IL-12, Sun et al investigated whether recombinant adenoviruses expressing IL-2 (rAd-IL-2) as a gene immunotherapy agent could optimize the prognosis of HCC patients (53). IL-2 treatment was the first immunotherapy approved by the US Food and Drug Administration for use in melanomas (105).…”

“…Importantly, using an oncolytic adenovirus is much safer than Lymphodepleting preconditioning with high-dose chemotherapy (106). According to Sun et al's study, rAd-IL-2 exhibits a significant induced anti-tumor immune response by recruiting CD4 + and CD8 + T cells, increasing the interferon-γ release, and stimulating cytotoxic T lymphocyte responses in the HCC tumor model (53).…”

Overexpression of TG2 enhances the differentiation of ectomesenchymal stem cells into neuron‑like cells and promotes functional recovery in adult rats following spinal cord injury

“…At present, the efficacy of available treatments remains largely unsatisfactory. However, thanks to advances in stem cell transplantation therapies, the situation is gradually improving as increasing evidence suggests that the treatment of traumatic nervous system damage is possible (27–29). Notably, the type of cell chosen is critical for the therapy efficacy.…”

Inflammasome-Mediated Cytokines: A Key Connection between Obesity-Associated NASH and Liver Cancer Progression

“…Promising cytokine immunotherapies currently under investigation are pegylated INF [ 117 ], INF-β [ 118 ], IL-2 in adenoviral vector [ 119 ], IL-6 [ 120 ], IL-7 [ 121 ], TNF-α [ 122 ], and TGF-beta [ 123 ]. In addition, intracellular biosignaling pathways related to cytokines are also a promising approach [ 124 ].…”