Prostate-specific antigen response and systemic T cell activation after insitu gene therapy in prostate cancer patients failing radiotherapy

Citation
Bj. Miles et al., Prostate-specific antigen response and systemic T cell activation after insitu gene therapy in prostate cancer patients failing radiotherapy, HUM GENE TH, 12(16), 2001, pp. 1955-1967
Citations number
26
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Molecular Biology & Genetics
Journal title
HUMAN GENE THERAPY
ISSN journal
1043-0342 → ACNP
Volume
12
Issue
16
Year of publication
2001
Pages
1955 - 1967
Database
ISI
SICI code
1043-0342(200111)12:16<1955:PARAST>2.0.ZU;2-#
Abstract
In an extended phase I/II study we evaluated 36 prostate cancer patients wi th local recurrence after radiotherapy who received single or repeated cycl es of replication-deficient adenoviral vector (ADV)-mediated herpes simplex virus-thymidine kinase (HSV-tk) plus ganciclovir (GCV) in situ gene therap y with respect to serum PSA levels, alterations in immune cells, and number s of apoptotic cells in needle biopsies. An initial cycle of HSV-tk plus GC V gene therapy caused a significant prolongation of the mean serum PSA-doub ling time (PSADT) from 15.9 to 42.5 months (p = 0.0271) and in 28 of the in jected patients (77.8%) there was a mean PSA reduction (PSAR) of 28%. It to ok a mean of 8.5 months for the PSA to return to the initial PSA (TR-PSA) v alue. 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 m onths). Moderately increased serum adenovirus antibody titers were generall y observed 2 weeks after initial vector injection. Also at this time there was a statistically significant increase in the mean percent of CD8(+) T ce lls positive for the HLA-DR marker of activation in peripheral blood (p = 0 .0088). Studies using prostate biopsies obtained at the same time point dem onstrated that vector DNA was detectable by PCR in most samples yet all pat ients remained positive for prostate cancer in at least one biopsy core. Fu rther 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 t herapy can be administered to prostate cancer patients who failed radiother apy and have a localized recurrence. Biological responses to this experimen tal therapy including increases in PSADT, PSAR, and TR-PSA, and activated C D8(+) T cells present in the peripheral blood, were demonstrated. Interesti ngly, the density of CD8(+) cells in posttreatment biopsies correlated with the number of apoptotic cells.