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IL-12 and IL-27 sequential gene therapy via intramuscular electroporation delivery for eliminating distal aggressive
Shiguo Zhu1, Dean Anthony Lee, Shulin Li
1School of Medicine, Institute of Medical Science, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
Abstract:
Eradication of residual malignancies and metastatic tumors via a systemic approach is the key for successfully treating cancer and increasing cancer patient survival. Systemic administration of IL-12 protein in an acute large dose is effective but toxic. Systemic administration of IL-12 gene by persistently expressing a low level of IL-12 protein may reduce the systemic toxicity but only eradicates IL-12-sensitive tumors. In this study, we discovered that sequential administration of IL-12- and IL-27-encoding DNA, referred to as sequential IL-12-->IL-27 (IL-12 administration followed by IL-27 administration 10 d after) gene therapy, not only eradicated IL-12-sensitive CT26 tumors from 100% of mice but also eradicated the highly malignant 4T1 tumors from 33% of treated mice in multiple independent experiments. This IL-12-->IL-27 sequential gene therapy is not only superior to IL-12-encoding plasmid DNA given a total of two times at a 10-d interval sequential gene therapy for eliminating tumors but also for inducing CTL activity, increasing T cell infiltration into tumors, and yielding a large number of tumor-specific IFN-gamma-positive CD8 T cells. Notably, depletion of either T or NK cells during the IL-27 treatment phase reverses tumor eradication, suggesting an NK cell requirement for this sequential gene therapy-mediated tumor eradication. Both reversal of the administration sequence and coadministration of IL-12 and IL-27 impaired tumor eradication in 4T1 tumor-bearing mice. This IL-12-->IL-27 sequential gene therapy, via sequential administration of IL-12- and IL-27-encoding plasmid DNA into tumor-bearing mice through i.m. electroporation, provides a simple but effective approach for eliminating inaccessible residual tumors.
Insights
Sequential gene therapy using Interleukin-12 (IL-12) and Interleukin-27 (IL-27) DNA successfully eradicated difficult tumors in mice. This novel approach shows promise for treating residual and metastatic cancers by enhancing immune responses.
Area of Science:
- Immunology
- Cancer Biology
- Gene Therapy
Background:
- Systemic cancer treatment requires eradicating residual and metastatic disease for improved survival.
- High-dose Interleukin-12 (IL-12) protein therapy is effective but toxic.
- Low-dose, persistent IL-12 expression via gene therapy reduces toxicity but has limited efficacy against certain tumors.
Purpose of the Study:
- To investigate the efficacy of sequential IL-12 and IL-27 gene therapy for eradicating established tumors.
- To compare sequential IL-12-->IL-27 gene therapy with other IL-12-based strategies.
- To elucidate the immune mechanisms underlying sequential IL-12-->IL-27 gene therapy-mediated tumor eradication.
Main Methods:
- Sequential administration of IL-12 and IL-27 encoding DNA via intramuscular electroporation in tumor-bearing mice.
- Evaluation of tumor eradication rates in CT26 and 4T1 tumor models.
- Assessment of cytotoxic T lymphocyte (CTL) activity, T cell infiltration, and cytokine production (IFN-gamma).
- Depletion studies involving T cells and Natural Killer (NK) cells to determine their roles.
Main Results:
- Sequential IL-12-->IL-27 gene therapy eradicated IL-12-sensitive CT26 tumors in 100% of mice.
- This therapy eradicated highly malignant 4T1 tumors in 33% of treated mice.
- Sequential IL-12-->IL-27 therapy outperformed single IL-12 DNA administration.
- Enhanced CTL activity, increased T cell infiltration, and elevated tumor-specific IFN-gamma-producing CD8 T cells were observed.
- Tumor eradication was reversed upon depletion of T or NK cells during the IL-27 phase, indicating their crucial role.
- Reversing the sequence or co-administering IL-12 and IL-27 impaired tumor eradication.
Conclusions:
- Sequential IL-12-->IL-27 gene therapy is a potent strategy for eradicating challenging tumors, including metastatic ones.
- The therapy enhances anti-tumor immunity through CTL and NK cell activation.
- This approach offers a simple yet effective method for treating inaccessible residual tumors.
