Induction of p53-regulated genes and tumor regression in lung cancer patients after intratumoral delivery of adenoviral p53 (INGN 201) and radiation therapy.
OBJECTIVE
We designed a prospective single arm Phase II study to evaluate the feasibility and mechanisms of apoptosis induction after Ad-p53 (INGN 201) gene transfer and radiation therapy in patients with non-small cell lung cancer.


METHODS
Nineteen patients with nonmetastatic non-small cell lung cancer who were not eligible for chemoradiation or surgery were treated as outpatients with radiation therapy to 60 Gy over 6 weeks in conjunction with three intratumoral injections of Ad-p53 (INGN 201) on days 1, 18, and 32.


RESULTS
Seventeen of 19 patients completed all planned radiation and Ad-p53 (INGN 201) gene therapy as outpatients. The most common adverse events were grade 1 or 2 fevers (79%) and chills (53%). Three months after completion of therapy, pathologic biopsies of the primary tumor revealed no viable tumor (12 of 19 patients, 63%), viable tumor (3 of 19 patients, 16%), and not assessed (4 of 19 patients, 21%). Computed tomography and bronchoscopic findings at the primary injected tumor revealed complete response (1 of 19 patients, 5%), partial response (11 of 19 patients, 58%), stable disease (3 of 19 patients, 16%), progressive disease (2 of 19 patients, 11%), and not evaluable (2 of 19 patients, 11%). Quantitative reverse transcription-PCR analysis of the four p53 related genes [p21 (CDKN1A), FAS, BAK, and MDM2] revealed that Bak expression was increased significantly 24 h after Ad-p53 (INGN 201) injection and levels of CDKN1A and MDM2 expression were increased over the course of treatment.


CONCLUSIONS
Intratumoral injection of Ad-p53 (INGN 201) in combination with radiation therapy is well tolerated and demonstrates evidence of tumor regression at the primary injected tumor. Serial biopsies of the tumor suggest that BAK gene expression is most closely related to Ad-p53 (INGN 201) gene transfer.
Swisher
Stephen G
SG
Department of Thoracic and Cardiovascular Surgery, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA. sswisher@mdanderson.org
Roth
Jack A
JA
Komaki
Ritsuko
R
Gu
Jian
J
Lee
J Jack
JJ
Hicks
Marshall
M
Ro
Jae Y
JY
Hong
Waun K
WK
Merritt
James A
JA
Ahrar
Kamaran
K
Atkinson
N Edward
NE
Correa
Arlene M
AM
Dolormente
Marcelo
M
Dreiling
Linda
L
El-Naggar
Adel K
AK
Fossella
Frank
F
Francisco
Rhodette
R
Glisson
Bonnie
B
Grammer
Susan
S
Herbst
Roy
R
Huaringa
Armando
A
Kemp
Bonnie
B
Khuri
Fadlo R
FR
Kurie
Jonathan M
JM
Liao
Zhongxio
Z
McDonnell
Timothy J
TJ
Morice
Rudolfo
R
Morello
Frank
F
Munden
Reginald
R
Papadimitrakopoulou
Vassiliki
V
Pisters
Katherine M W
KM
Putnam
Joe B
JB
Sarabia
Arcenio J
AJ
Shelton
Thomas
T
Stevens
Craig
C
Shin
Daniel M
DM
Smythe
William R
WR
Vaporciyan
Ara A
AA
Walsh
Garrett L
GL
Yin
Min
M
D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D003131:Combined Modality Therapy; D005260:Female; D018014:Gene Transfer Techniques; D016158:Genes, p53; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D011878:Radiotherapy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53