Prostate-specific antigen response and systemic T cell activation after in situ gene therapy in prostate cancer patients failing radiotherapy.
In an extended phase I/II study we evaluated 36 prostate cancer patients with local recurrence after radiotherapy who received single or repeated cycles of replication-deficient adenoviral vector (ADV)-mediated herpes simplex virus-thymidine kinase (HSV-tk) plus ganciclovir (GCV) in situ gene therapy with respect to serum PSA levels, alterations in immune cells, and numbers of apoptotic cells in needle biopsies. An initial cycle of HSV-tk plus GCV gene therapy caused a significant prolongation of the mean serum PSA-doubling time (PSADT) from 15.9 to 42.5 months (p = 0.0271) and in 28 of the injected patients (77.8%) there was a mean PSA reduction (PSAR) of 28%. It took a mean of 8.5 months for the PSA to return to the initial PSA (TR-PSA) value. A repeated cycle of gene therapy failed to significantly extend PSADT but did result in significant increases in PSAR (29.4%) and TR-PSA (10.5 months). Moderately increased serum adenovirus antibody titers were generally observed 2 weeks after initial vector injection. Also at this time there was a statistically significant increase in the mean percent of CD8(+) T cells positive for the HLA-DR marker of activation in peripheral blood (p = 0.0088). Studies using prostate biopsies obtained at the same time point demonstrated that vector DNA was detectable by PCR in most samples yet all patients remained positive for prostate cancer in at least one biopsy core. Further analysis demonstrated a correlation between the level of CD8(+) cells and the number of apoptotic cells in biopsies containing cancer cells (p = 0.042). We conclude that repeated cycles of in situ HSV-tk plus GCV gene therapy can be administered to prostate cancer patients who failed radiotherapy and have a localized recurrence. Biological responses to this experimental therapy including increases in PSADT, PSAR, and TR-PSA, and activated CD8(+) T cells present in the peripheral blood, were demonstrated. Interestingly, the density of CD8(+) cells in posttreatment biopsies correlated with the number of apoptotic cells.
Miles
B J
BJ
Matsunaga-Conte Prostate Cancer Research Center, Scott Department of Urology, Baylor College of Medicine, Houston, TX 77030, USA.
Shalev
M
M
Aguilar-Cordova
E
E
Timme
T L
TL
Lee
H M
HM
Yang
G
G
Adler
H L
HL
Kernen
K
K
Pramudji
C K
CK
Satoh
T
T
Gdor
Y
Y
Ren
C
C
Ayala
G
G
Wheeler
T M
TM
Butler
E B
EB
Kadmon
D
D
Thompson
T C
TC
D000256:Adenoviridae / Q000235:genetics; D000368:Aged; D000914:Antibodies, Viral / Q000097:blood; D000998:Antiviral Agents / Q000008:administration & dosage; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D017931:DNA Primers; D015774:Ganciclovir / Q000008:administration & dosage; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D008297:Male; D009364:Neoplasm Recurrence, Local; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics
D000914:Antibodies, Viral; D000998:Antiviral Agents; D017931:DNA Primers; D013937:Thymidine Kinase; D017430:Prostate-Specific Antigen; D015774:Ganciclovir