A phase I study of adenovirus-mediated wild-type p53 gene transfer in patients with advanced non-small cell lung cancer.
Mutations of the tumor suppressor gene p53 are the most common genetic alterations observed in human cancer. Loss of wild-type p53 function impairs cell cycle arrest as well as repair mechanisms involved in response to DNA damage. Further, apoptotic pathways as induced by radio- or chemotherapy are also abrogated. Gene transfer of wild-type p53 was shown to reverse these deficiencies and to induce apoptosis in vitro and in preclinical in vivo tumor models. A phase I dose escalation study of a single intratumoral injection of a replication-defective adenoviral expression vector encoding wild-type p53 was carried out in patients with incurable non-small cell lung cancer. All patients enrolled had p53 protein overexpression as a marker of mutant p53 status in pretreatment tumor biopsies. Treatment was performed either by bronchoscopic intratumoral injection or by CT-guided percutaneous intratumoral injection of the vector solution. Fifteen patients were enrolled in two centers, and were treated at four different dose levels ranging from 10(7) to 10(10) PFU (7.5 x 10(9) to 7.5 x 10(12) particles). No clinically significant toxicity was observed. Successful transfer of wild-type p53 was achieved only with higher vector doses. Vector-specific wild-type p53 RNA sequences could be demonstrated in posttreatment biopsies of six patients. Transient local disease control by a single intratumoral injection of the vector solution was observed in four of those six successfully transduced patients. There was no evidence of clinical responses at untreated tumor sites. Wild-type p53 gene therapy by intratumoral injection of a replication-defective adenoviral expression vector is safe, feasible, and biologically effective in patients with advanced non-small cell lung cancer.
Department of Medicine III, Johannes Gutenberg University, Mainz, Germany.
M
M
Schuler
C
C
Rochlitz
J A
JA
Horowitz
J
J
Schlegel
A P
AP
Perruchoud
F
F
Kommoss
C T
CT
Bolliger
H U
HU
Kauczor
P
P
Dalquen
M A
MA
Fritz
S
S
Swanson
R
R
Herrmann
C
C
Huber
D000256:Adenoviridae / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018014:Gene Transfer Techniques / Q000009:adverse effects; D016158:Genes, p53 / Q000235:genetics*; D015316:Genetic Therapy / Q000009:adverse effects / Q000706:statistics & numerical data*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007267:Injections / Q000379:methods; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009026:Mortality; D012333:RNA, Messenger / Q000235:genetics; D016896:Treatment Outcome
D012333:RNA, Messenger