TNFerade, an adenovector carrying the transgene for human tumor necrosis factor alpha, for patients with advanced solid tumors: surgical experience and long-term follow-up.
BACKGROUND
Over the last several years, attempts have been made to use the tumoricidal effects of tumor necrosis factor (TNF)-alpha to treat cancer. Many of these studies demonstrated dose-limiting systemic side effects from high concentrations of TNF-alpha. The recent focus has been on developing a local delivery system for TNF-alpha to minimize the systemic response.


METHODS
This study was part of a phase I open-label multi-institutional trial using TNFerade. We focus on the patients treated at Baylor University Medical Center and provide postoperative and long-term follow-up. TNFerade uses a second-generation nonreplicating adenovirus as the vector for delivery of the human transgene TNF-alpha. An early growth response 1 promoter was placed upstream from the TNF-alpha gene. This promoter is activated by ionizing radiation, thus allowing for temporal and spatial control of TNF-alpha release. Tumors were injected over 5 weeks with ionizing radiation given 3 days after injections for 6 weeks. Tumor response was measured by computed tomographic imaging and physical examination.


RESULTS
As described in our original experience, no patients experienced dose-limiting toxicities up to doses of 4 x 10(11) particles per injection. Tumors injected demonstrated a response independently of histology. Four patients had complete regression of the tumor injected. Three patients with complete regression have survived > or = 2 years from the time of treatment.


CONCLUSIONS
Both short-term and long-term safety are observed with TNFerade. These data demonstrate the need for phase II trials.
McLoughlin
James M
JM
Department of Surgery, Sammons Cancer Center of Baylor University Medical Center, Worth Street #420, Dallas, Texas 75246, USA.
McCarty
Todd M
TM
Cunningham
Casey
C
Clark
Valerie
V
Senzer
Neil
N
Nemunaitis
John
J
Kuhn
Joseph A
JA
D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000368:Aged; D005260:Female; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000601:surgery; D011401:Promoter Regions, Genetic; D019076:Transgenes; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000627:therapeutic use*
D014409:Tumor Necrosis Factor-alpha