Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small-cell lung cancer.
OBJECTIVE
To determine the safety and tolerability of adenovirus-mediated p53 (Adp53) gene transfer in sequence with cisplatin when given by intratumor injection in patients with non-small-cell lung cancer (NSCLC).


METHODS
Patients with advanced NSCLC and abnormal p53 function were enrolled onto cohorts receiving escalating dose levels of Adp53 (1 x 10(6) to 1 x 10(11) plaque-forming units [PFU]). Patients were administered intravenous cisplatin 80 mg/m(2) on day 1 and study vector on day 4 for a total of up to six courses (28 days per course). Apoptosis was determined by the terminal deoxynucleotidyl- transferase-dUTP nick-end labeling assay. Evidence of vector-specific sequences were determined using reverse-transcriptase polymerase chain reaction. Vector dissemination and biodistribution was monitored using a series of assays (cytopathic effects assay, Ad5 hexon enzyme-linked immunosorbent assay, vector-specific polymerase chain reaction assay, and antibody response assay).


RESULTS
Twenty-four patients (median age, 64 years) received a total of 83 intratumor injections with Adp53. The maximum dose administered was 1 x 10(11) PFU per dose. Transient fever related to Adp53 injection developed in eight of 24 patients. Seventeen patients achieved a best clinical response of stable disease, two patients achieved a partial response, four patients had progressive disease, and one patient was not assessable. A mean apoptotic index between baseline and follow-up measurements increased from 0.010 to 0.044 (P =.011). Intratumor transgene mRNA was identified in 43% of assessable patients.


CONCLUSIONS
Intratumoral injection with Adp53 in combination with cisplatin is well tolerated, and there is evidence of clinical activity.
Nemunaitis
J
J
US Oncology, Baylor University Medical Center, Dallas, TX, USA. j.nemunaitis@usoncology.com
Swisher
S G
SG
Timmons
T
T
Connors
D
D
Mack
M
M
Doerksen
L
L
Weill
D
D
Wait
J
J
Lawrence
D D
DD
Kemp
B L
BL
Fossella
F
F
Glisson
B S
BS
Hong
W K
WK
Khuri
F R
FR
Kurie
J M
JM
Lee
J J
JJ
Lee
J S
JS
Nguyen
D M
DM
Nesbitt
J C
JC
Perez-Soler
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R
Pisters
K M
KM
Putnam
J B
JB
Richli
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Shin
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DM
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Roth
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D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology; D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D018014:Gene Transfer Techniques / Q000009:adverse effects; D016158:Genes, p53; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D020287:In Situ Nick-End Labeling; D015552:Injections, Intralesional; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009928:Organ Specificity / Q000235:genetics; D013194:Staining and Labeling
D000914:Antibodies, Viral; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D002945:Cisplatin