Phase I trial of intratumoral liposome E1A gene therapy in patients with recurrent breast and head and neck cancer.
OBJECTIVE
We conducted a Phase 1 study to determine the maximal tolerated dose and maximum biologically active dose of the E1A gene delivered by intratumoral injection as a lipid complex with 3 beta[N-(n',n'-dimethylaminoethane)-carbamoyl] cholesterol/dioleoylphosphatidyl-ethanolamine (tgDCC-E1A). The E1A adenovirus gene functions as a tumor inhibitor gene by repressing oncogene transcription; modulating gene expression, resulting in cellular differentiation; and inducing apoptosis of cancer cells. E1A also sensitizes cancer cells to chemotherapeutic drugs such as etoposide, cisplatin, and taxol.


METHODS
Nine patients with recurrent and unresectable breast cancer and nine patients with head and neck cancer were enrolled. One tumor nodule in each patient was injected with tgDCC-E1A. Safety, tumor response, E1A gene transfer, and down-regulation of HER-2/neu were evaluated.


RESULTS
No dose-limiting toxicity was observed in the four dose groups (15, 30, 60, and 120 microg DNA/cm of tumor). All patients tolerated the injections, although several experienced pain and bleeding at the injection site. A maximally tolerated dose was not reached in this study. E1A gene transfer was demonstrated in 14 of 15 tumor samples tested, and down-regulation of HER-2/neu was demonstrated in two of the five patients who overexpressed HER-2/neu at baseline. HER-2/neu could not be assessed in other posttreatment tumor samples because of extensive necrosis. In one breast cancer patient, no pathological evidence of tumor was found on biopsy of the treated tumor site at week 12. In 16 patients evaluable for tumor response, 2 had minor responses, 8 had stable disease, and 6 had progressive disease.


CONCLUSIONS
Gene therapy with an E1A gene:lipid complex appears to be safe and warrants further testing.
Yoo
G H
GH
Departments of Otolaryngology-Head and Neck Surgery, Wayne State University-Karmanos Cancer Institute, Detroit, Michigan 48201, USA.
Hung
M C
MC
Lopez-Berestein
G
G
LaFollette
S
S
Ensley
J F
JF
Carey
M
M
Batson
E
E
Reynolds
T C
TC
Murray
J L
JL
D017500:Adenovirus E1A Proteins / Q000009:adverse effects / Q000235:genetics / Q000627:therapeutic use*; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics / Q000628:therapy*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000628:therapy*; D006801:Humans; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012008:Recurrence; D014162:Transfection; D016896:Treatment Outcome
D017500:Adenovirus E1A Proteins; D004337:Drug Carriers; D008081:Liposomes; D018719:Erb-b2 Receptor Tyrosine Kinases