Biological Response Determinants in HSV-tk + Ganciclovir Gene Therapy for Prostate Cancer

Abstract

The limitations of current forms of prostate cancer therapy have driven researchers to search for new alternatives. Previously we showed cytopathic effect related to HSV-tk in prostate cancer. In this study we present initial results of a neoadjuvant HSV-tk gene therapy trial and address some of the potential mechanistic aspects of its effect in human tissues. We enrolled 23 men with clinically localized prostate cancer but high risk for recurrence in this Phase I-II trial. Intraprostatic viral injections (one to four) were followed by 2 weeks of ganciclovir and prostatectomy 2-4 weeks later. Toxicity was modest. Surgical specimens were embedded fully and whole-mount slides were imaged and analyzed for areas of cytopathic effect. The larger the tumor the greater the cytopathic effect. The effect also seems to be related to areas of high CAR expression. However, the number of injection sites did not influence effect. Local (CD8+ cells and macrophages) and systemic immune response (CD8+ and activated CD8+, IL-12) was increased in patients treated with HSV-tk. Increased apoptosis and decreased microvessel density were also noted in these patients. The results suggest a tumor-specific effect mediated by systemic and local immune response, antiangiogenic effect, and modulation of apoptosis.

Cooperative effects of adenoviral vector-mediated interleukin 12 gene therapy with radiotherapy in a preclinical model of metastatic prostate cancer

“…29 Interestingly, there was a concomitant decrease in the plasma levels of TGF-b1. 29 In our preclinical studies of AdmIL-12 gene therapy for orthotopic murine prostate tumors generated by the RM-9 tumor cell line, a single orthotopic injection of AdmIL-12 significantly suppressed tumor growth, increased the survival time, suppressed pre-established lung metastases, and reduced the number of spontaneous regional lymph node metastases.…”

“…29 Interestingly, there was a concomitant decrease in the plasma levels of TGF-b1. 29 In our preclinical studies of AdmIL-12 gene therapy for orthotopic murine prostate tumors generated by the RM-9 tumor cell line, a single orthotopic injection of AdmIL-12 significantly suppressed tumor growth, increased the survival time, suppressed pre-established lung metastases, and reduced the number of spontaneous regional lymph node metastases. 13 We have also demonstrated that orthotopic AdmIL-12 is as effective as a vector that combines IL-12 with the co-stimulatory molecule CD80 (B7-1) for suppression of lung metastases, but not quite as effective for survival.…”

NT-polyplex: a new tool for therapeutic gene delivery to neuroblastoma tumors

“…42 The use of the HSVTK-GCV system in human trials to cause the death of tumoral cells has not been efficient. [43][44][45][46] A recently improved HSVTK system based on the TK30 mutant is able to increase the killing efficacy of GCV and the bystander effect on animal models of human tumor cells up to 500-fold. 47 The combination of this system with the expression of exogenous wild-type p53 seems to be optimum for clinical trials of suicide-gene therapy of tumoral cells.…”

Secretable Chaperone Grp170 Enhances Therapeutic Activity of a Novel Tumor Suppressor, mda-7/IL-24

“…Among the solid tumors, CaP is ideally suited for the first test of efficacy of this idea because this nonessential organ expresses a wide array of unique antigens and highly accessible to gene transfer by using digital or transrectal ultrasound guidance (37). Primary CaP is relatively slow growing and thus sequential gene therapy approaches can be incorporated safely into treatment strategies.…”