Optimization and toxocologic effects of cancer immuno-electrogene therapy using a tumor-targeted interleukin-12 gene construct

This dissertation includes a comprehensive current review of reversible electroporation (EP) and other related physical gene transfection techniques; an overview of results of electrochemogene therapy (ECGT) used to treat naturally occurring spontaneous neoplasms in dogs; and the results of comprehensive, pre-clinical toxicology testing of electrogene therapy (EGT) of a tumor-targeted version of interleukin-12 (IL-12) in mice. Intralesional bleomycin (BLM) and feline interleukin-12 (fIL-12) DNA injection combined with trans-lesional EP resulted in complete cure of two recurrent oral squamous cell carcinomas and an acanthomatous ameloblastoma in a series of six cases of spontaneous neoplasia in pet dogs. The three remaining dogs, which had no other treatment options, had partial responses to ECGT. One of these dogs had mandibular melanoma with pulmonary and lymph node metastases; one dog had cubital histiocytic sarcoma with spleen metastases; and one had soft palate fibrosarcoma. Treatment of all six dogs was associated with minimal side effects, was easy to perform, was associated with repair of bone lysis in cured dogs; improved the quality of life for dogs with partial responses; and extended overall survival time. For the purpose of meeting pre-clinical safety requirements for an Investigational New Drug filing, we assessed the safety of tumor-targeted interleukin-12 (ttIL-12) when administered by EGT in C3H/HeJ mice by identifying an initial safe dose for human dose escalation schemes, toxicity target organs, markers of toxicity, and toxicity reversibility. Dystrophic cardiac calcification in older, 5 ìg ttIL-12-treated mice was the only serious toxicity. Based on these results and the lack of any effect on wound healing when combined with surgery, low-intensity EGT with ttIL-12 appears to be safe and well tolerated as both a single treatment modality and when combined with surgical tumor resection.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Medicine and Health Sciences

Grantor

Biomedical and Veterinary Medical Sciences - Comparative Biomedical Sciences

Year dc:date.available

2010

Author dc:creator

• Reed, Scott Douglas

• cancer
• gene therapy
• interleukin 12
• toxicity
• cytokine

Statement dc:rights

• unrestricted
• Release the entire work immediately for access worldwide.

Identifier

etd-11172010-085322
https://repository.lsu.edu/gradschool_dissertations/657

OAI identifier oai:identifier

oai:repository.lsu.edu:gradschool_dissertations-1656