Title page for ETD etd-11172010-085322


Type of Document Dissertation
Author Reed, Scott Douglas
Author's Email Address sreed@vetmed.lsu.edu
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
  • cancer
  • gene therapy
  • interleukin 12
  • toxicity
  • cytokine
Date of Defense 2010-11-05
Availability unrestricted
Abstract
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 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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