Biological activity and safety of adenoviral vector-expressed wild-type p53 after intratumoral injection in melanoma and breast cancer patients with p53-overexpressing tumors

p53 mutations are common genetic alterations in human cancer. Gene transfer of a wild-type (wt) p53 gene reverses the loss of normal p53 function in v itro and in vivo. A phase I dose escalation study of single intratumoral (i .t.) injection of a replication-defective adenoviral expression vector cont aining wt p53 was carried out in patients with metastatic melanoma or breas t cancer with increased p53 protein immunoreactivity in pretreatment tumor biopsies. The biological activity of the injected wt p53 was assayed by rev erse transcriptase-polymerase chain reaction in tumor tissue. A total of si x (five melanoma and one breast adenocarcinoma) patients were treated at do se levels dependent upon tumor size/dose escalation sequence. Five of six p atients became positive for the transfer of wt p53 into tumor tissue 2 days after injection of the vector. Of the four patients assayed, all developed anti-adenoviral antibodies. Adverse reactions associated with i.t. injecti on were mild, with no obvious correlation between the incidence, severity, or relationship of the events and drug dose, p53 gene therapy by i.t. injec tion of a replication-defective adenoviral expression vector is safe, feasi ble, and biologically effective (with respect to transduction frequency) in patients with either metastatic melanoma or breast cancer.