The conventional therapies like surgery and radiation are effective in eliminating large volume tumors but it is not practical to employ these approaches for treating the systemic residual microscopic malignancy. Chemotherapy may be effective in inhibiting or eliminating the systemic residual microscopic malignancy but recurrence eventually occurs due to the development of drug resistance. Delivery of cytokine gene, like IL-12, via electroporation not only eradicates residual tumors but also prevents tumor recurrence. However, monocytokine electroporation gene therapy generally only eliminates in the less aggressive tumors. For example, neither electroporation IL-12 nor other cytokine genes alone can eradicate the highly malignant 4T1 breast adenocarcinoma via systemic administration. To eradicate the highly malignant tumors, multiple systemic approaches have been tested using our unique electroporation-based gene delivery and gene expression systems during the current award period. We discovered that sequential systemic expression of IL-12 and IL-27 eradicates not only the less aggressive CT26 colon tumors but also highly malignant 4T1 breast tumors. The cured mice reject rechallenged homologous tumor cells in 83% of mice. Intriguingly, this potent therapeutic efficacy cannot be achieved by both IL-12 and IL-27 sequential gene therapy in a reversed order of administration and co-administration of IL-12 and IL-27. Therefore, one of goals in this application is to elucidate why IL-27 electroporation gene therapy is required after IL-12 electroporation gene therapy for eradicating tumors. We also found that doxorubicin, an anti-neoplasm drug, potentiates IL-12- mediated eradication of highly malignant 4T1 tumors and induces the accumulation of the toxicity- inducing cytokine IFN into tumors but not in the normal tissues. Because both Dox plus IL-12 and IL- 12/IL27 sequential gene therapy independently induces eradication of this highly malignant 4T1 tumors from ~30% mice, it is likely a combination of both will further improve the therapeutic efficacy. Because the IL-12-induced toxicity-inducing cytokine IFN will be accumulated in tumors by Dox treatment, inclusion of Dox in the sequential IL-12 and IL-27 electroporation gene therapy may increase the safety. Therefore, the applicant will determine the therapeutic efficacy and the safety of the sequential systemic IL-12 and IL-27 electroporation gene therapy in combination with Dox treatment. A positive result will support the central hypothesis that the sequential systemic IL-12 and IL-27 gene therapy in combination with Dox is an effective approach for eliminating residual microscopic malignancy and will reduce the systemic IL-12 treatment-caused toxicity.

Public Health Relevance

Tumor recurrence and metastatic tumors are the primary mechanisms to cause death of the cancer patients. None of the existing systemic conventional therapy eliminates highly malignant residual microscopic malignancy and metastatic tumors. In this application, the applicant proposes developing a programmed immunostimulatory gene therapy for safely treating tumors. This study will be highly beneficial for cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA098928-10
Application #
8299144
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Yovandich, Jason L
Project Start
2002-08-09
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
10
Fiscal Year
2012
Total Cost
$311,816
Indirect Cost
$114,464
Name
University of Texas MD Anderson Cancer Center
Department
Pediatrics
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Wang, Xiaohong; Li, Shulin (2014) Protein mislocalization: mechanisms, functions and clinical applications in cancer. Biochim Biophys Acta 1846:13-25
Hu, Jiemiao; Zhu, Shiguo; Xia, Xueqing et al. (2014) CD8+T cell-specific induction of NKG2D receptor by doxorubicin plus interleukin-12 and its contribution to CD8+T cell accumulation in tumors. Mol Cancer 13:34
Dibra, Denada; Cutrera, Jeffry; Xia, Xueqing et al. (2012) Interleukin-30: a novel antiinflammatory cytokine candidate for prevention and treatment of inflammatory cytokine-induced liver injury. Hepatology 55:1204-14
Dibra, Denada; Cutrera, Jeffry J; Li, Shulin (2012) Coordination between TLR9 signaling in macrophages and CD3 signaling in T cells induces robust expression of IL-30. J Immunol 188:3709-15
Satelli, Arun; Li, Shulin (2011) Vimentin in cancer and its potential as a molecular target for cancer therapy. Cell Mol Life Sci 68:3033-46
Dibra, Denada; Cutrera, Jeffry; Xia, Xueqing et al. (2011) WSX1 expression in tumors induces immune tolerance via suppression of effector immune cells. PLoS One 6:e19072
Zhu, Shiguo; Lee, Dean Anthony; Li, Shulin (2010) IL-12 and IL-27 sequential gene therapy via intramuscular electroporation delivery for eliminating distal aggressive tumors. J Immunol 184:2348-54
Liu, Jianguo; Xia, Xueqing; Torrero, Marina et al. (2006) The mechanism of exogenous B7.1-enhanced IL-12-mediated complete regression of tumors by a single electroporation delivery. Int J Cancer 119:2113-8
Torrero, Marina N; Henk, William G; Li, Shulin (2006) Regression of high-grade malignancy in mice by bleomycin and interleukin-12 electrochemogenetherapy. Clin Cancer Res 12:257-63
Torrero, Marina N; Xia, Xueqing; Henk, Williams et al. (2006) Stat1 deficiency in the host enhances interleukin-12-mediated tumor regression. Cancer Res 66:4461-7

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