Therapy of cancer by cytokines mediated by gene therapy approach

Area of Science:

• Oncology
• Gene Therapy
• Immunotherapy

Background:

• Gene therapy using immunostimulatory cytokines has shown success in animal cancer models but limited efficacy in human clinical trials.
• Improved gene transfer vector systems are crucial for advancing cancer gene therapy.
• Hepatocellular carcinoma (HCC) remains a significant challenge requiring novel therapeutic strategies.

Purpose of the Study:

• To develop and evaluate novel gene transfer vector systems for enhanced cancer gene therapy.
• To assess the efficacy and safety of hybrid viral vectors and inducible adenovirus vectors expressing interleukin-12 (IL-12) in preclinical cancer models.
• To explore the potential of oncolytic adenoviruses combined with transgene expression for potent antitumor activity.

Main Methods:

• Construction of a hybrid viral vector (SFV replicon) encoding murine IL-12 (mIL-12) or LacZ.
• Development of helper-dependent adenovirus vectors with a mifepristone (RU486) inducible system for liver-specific expression of human IL-12 (hIL-12) or mIL-12.
• Insertion of cytokine genes into conditional replicative adenoviruses (oncolytic adenoviruses).
• In vitro and in vivo evaluation in hepatocellular carcinoma (HCC) and rat orthotropic liver tumor models.
• Assessment of tumor regression, anti-tumor activity, and toxicity.

Main Results:

• The hybrid viral vector demonstrated specific, high-level expression in HCC and potent anti-tumor activity in a rat liver tumor model without toxicity.
• Helper-dependent adenovirus vectors achieved sustained serum levels of hIL-12 with repetitive induction over 48 weeks.
• Treatment with HD-Ad/RUmIL-12 and RU486 resulted in complete regression of liver metastases in all animals.
• Oncolytic adenoviruses combined with transgene expression showed potential for strong antitumor activity through cytopathic and biological effects.

Conclusions:

• Novel gene therapy vectors, including hybrid viral vectors and inducible/oncolytic adenoviruses, show significant potential for effective and safe cancer treatment.
• Controlled and sustained expression of immunostimulatory cytokines like IL-12 via advanced vector systems can lead to complete tumor regression.
• These engineered viral vectors represent promising tools for future cancer gene therapy strategies, offering improved efficacy and safety profiles.