Biological activities of a recombinant adenovirus p53 (SCH 58500) administered by hepatic arterial infusion in a Phase 1 colorectal cancer trial.
The major focus of intrahepatic arterial (IHA) administration of adenoviruses (Ad) has been on safety. Currently, there is little published data on the biological responses to Ad when administered via this route. As part of a Phase I study, we evaluated biological responses to a replication-defective adenovirus encoding the p53 transgene (SCH 58500) when administered by hepatic arterial infusion to patients with primarily colorectal cancer metastatic to the liver. In analyzing biological responses to the Ad vector, we found that both total and neutralizing Ad antibodies increased weeks after SCH 58500 infusion. The fold increase in antibody titers was not dependent on SCH 58500 dosage. The proinflammatory cytokine interleukin-6 (IL-6) transiently peaked within 6 h of dosing. The cytokine sTNF-R2 showed elevation by 24 h post-treatment, and fold increases were directly related to SCH 58500 doses. Cytokines TNF-alpha, IL-1beta, and sTNF-R1 showed no increased levels over 24 h. Predose antibody levels did not appear to predict transduction, nor did serum Ad neutralizing factor (SNF). Delivery of SCH 58500 to tumor tissue occurred, though we found distribution more predominantly in liver tissues, as opposed to tumors. RT-PCR showed significantly higher expression levels (P<0.0001, ANOVA) for adenovirus type 2 and 5 receptor (CAR) in liver tissues, suggesting a correlation with transduction. Evidence of tumor-specific apoptotic activity was provided by laser scanning cytometry, which determined a coincidence of elevated nuclear p53 protein expression with apoptosis in patient tissue. IHA administration of a replication defective adenovirus is a feasible mode of delivery, allowing for exogenous transfer of the p53 gene into target tissues, with evidence of functional p53. Limited and transient inflammatory responses to the drug occurred, but pre-existing immunity to Ad did not preclude SCH 58500 delivery.
Atencio
I A
IA
Canji, Inc., San Diego, CA, USA. isabella.atencio@canji.com
Grace
M
M
Bordens
R
R
Fritz
M
M
Horowitz
J A
JA
Hutchins
B
B
Indelicato
S
S
Jacobs
S
S
Kolz
K
K
Maneval
D
D
Musco
M L
ML
Shinoda
J
J
Venook
A
A
Wen
S
S
Warren
R
R
D000256:Adenoviridae / Q000235:genetics*; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000914:Antibodies, Viral / Q000097:blood; D017209:Apoptosis / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology* / Q000628:therapy*; D016207:Cytokines / Q000097:blood; D017931:DNA Primers; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006499:Hepatic Artery; D006801:Humans; D007261:Infusions, Intra-Arterial; D047569:Laser Scanning Cytometry; D008113:Liver Neoplasms / Q000556:secondary*; D008297:Male; D008875:Middle Aged; D011991:Receptors, Virus / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000914:Antibodies, Viral; D016207:Cytokines; D017931:DNA Primers; D011991:Receptors, Virus; C085301:adenovirus receptor