LOS ANGELES--Preliminary results with a gene-therapy approach to
recurrent prostate cancer suggest antitumor activity in at least some
patients. Three of 18 patients have had decreases in PSA levels of
more than 50%. The effects have persisted for 45 to 290 days,
including one patient who became biopsy negative for a brief period
"The results suggest this is a real response, not a transient
episode related to inflammation," Peter Scardino, MD, chairman
of urology, Baylor College of Medicine, Houston, said at an ASCO
integrated symposium on prostate cancer.
For the past 3 years, the Baylor group has evaluated the therapeutic
potential of the herpes simplex virus-thymidine kinase (HSV-TK) gene
delivered to prostate cancer cells by a replication-deficient
adenoviral vector, followed by IV ganciclovir (Cytovene). Preclinical
studies showed that the HSV-TK gene penetrated 10% to 15% of cells in
culture but induced a cell-killing rate of about 99% because of a
profound "bystander effect" in surrounding tumor cells, he said.
Clinical investigation began last year. All patients selected for the
initial safety trial had biopsy-proven recurrence after primary
radiotherapy for clinically localized disease. The patients had
rising PSA levels but no evidence of metastases. None had received
hormonal therapy. "We selected these patients for the trial
because currently there is no standard treatment for this group,"
Dr. Scardino said.
Intralesional injection of the HSV-TK gene complex began at a dose of
1 × 108 IU, and ganciclovir was given at an IV dose
of 5 mg/kg twice a day for 2 weeks. This dose caused "absolutely
no evidence of toxicity" but also had no apparent effect on
tumors, Dr. Scardino said. Thus, he requested and received permission
from the FDA to increase the HSV-TK dosage until toxicity did appear.
Dr. Scardino said that 18 patients have received the HSV-TK gene at
doses ranging from 1 × 108 to 1 × 1011
IU. Three patients have had what the investigators interpret as
responses to the therapy.
The first response occurred in a patient who received 1 × 109
IU of HSV-TK. One response occurred at 1 × 1010, and
the third at 1 × 1011. Response was defined as a PSA
decline of 50% or more. One patient temporarily became biopsy
negative, and biopsy specimens revealed a marked evidence of tumor necrosis.
Toxicity has been minimal in the ongoing trial. Principal side
effects have included chills and fever. One patient developed grade
IV toxicity in the form of thrombocytopenia and abnormal liver
function. The platelet count dropped to 10,000 in this patient,
necessitating platelet transfusion.
No evidence of viral shedding from the adenoviral vector has appeared
in cultures or in blood. The vector did appear in the urine of eight
patients, and in a semen sample in the one patient who could provide
semen. Two patients had low levels of antiadenoviral antibodies.
Continuation of the phase I trial will test the safety of a second
injection of the HSV-TK gene and injection of multiple tumor sites.
"In the future, I think theres an opportunity to look at
combinations involving gene therapy and androgen ablation in patients
who are going to be treated with radiotherapy," Dr. Scardino
said. "We already have excellent results of combination therapy
in animal models of prostate cancer."