Type of Document Dissertation Author Reed, Scott Douglas Author's Email Address email@example.com URN etd-11172010-085322 Title Optimization and Toxocologic Effects of Cancer Immuno-electrogene Therapy Using a Tumor-Targeted Interleukin-12 Gene Construct Degree Doctor of Philosophy (Ph.D.) Department Comparative Biomedical Sciences (Veterinary Medical Sciences) Advisory Committee
Advisor Name Title Li, Shulin Committee Co-Chair Sehgal, Inder Committee Co-Chair Morgan, Timothy Committee Member Wakamatsu, Nobuko Committee Member Prosanta Chakrabarty Dean's Representative Keywords
- gene therapy
- interleukin 12
Date of Defense 2010-11-05 Availability unrestricted AbstractThis 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 ėg 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.
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