Adenoviral vector-mediated RTVP-1 gene-modified tumor cell-based vaccine suppresses the development of experimental prostate cancer

Abstract

We previously identified a novel p53 target gene, RTVP-1, that possesses unique cytotoxic and immunostimulatory activities which make it potentially useful for cancer gene therapy. To test the therapeutic potential of RTVP-1 in a gene-modified tumor cell-based vaccine model, we used an adenoviral vector capable of efficient transduction and expression of RTVP-1 (AdRTVP-1), together with a highly metastatic mouse prostate cancer cell line (178-2 BMA). A vaccine was prepared with 178-2 BMA cells transduced with AdRTVP-1 or a control adenoviral vector expressing b-galactosidase (Adbgal). After irradiation of the cells, syngeneic 129/Sv mice were vaccinated three times at weekly intervals. After 3 weeks, they were challenged with orthotopic 178-2 BMA cells. After 21 days, fewer than 60% of the RTVP-1-cell-vaccinated mice developed tumors compared to 100% of the control mice. The RTVP-1-cell vaccine significantly reduced primary tumor wet weight compared with control Adbgal-cell vaccine (Po0.0001 at 7 and 14 days). Experimental metastasis to lung was also significantly reduced (P ¼ 0.0377), and survival significantly increased (P ¼ 0.0002). In addition, significantly increased NK and CTL activities were demonstrated in the AdRTVP-1-cell-vaccinated mice. These findings indicate that RTVP-1 gene-modified cell-based vaccines may be useful in the prevention of recurrent prostate cancer.

Glioma Pathogenesis-Related Protein 1 Exerts Tumor Suppressor Activities through Proapoptotic Reactive Oxygen Species–c-Jun–NH2 Kinase Signaling

“…A tumor suppressor function for GLIPR1 is also supported by previous studies of the effects of GLIPR1 overexpression both in vitro and in vivo (4)(5)(6)(7)17); however, direct genetic evidence of such function was lacking until this study. We now show that Figure 4.…”

“…Functional analysis revealed that overexpression of either Glipr1 or GLIPR1 induces apoptosis and suppresses colony formation in vitro in various mouse and human cancer cell lines, independently of p53 status (4,5). Adenoviral vector-mediated delivery of Glipr1 into orthotopic mouse prostate cancer significantly suppressed tumor growth and metastasis to lung (6), whereas administration of a novel Glipr1 gene modified tumor cell vaccine to mice had significant antitumor activity in a preclinical model of recurrent prostate cancer (7). Adenoviral vectormediated GLIPR1 gene therapy is currently in a phase I/phase II clinical trial (IND13033), and GLIPR1 protein therapy is in preclinical development.…”

The CAP Superfamily: Cysteine-Rich Secretory Proteins, Antigen 5, and Pathogenesis-Related 1 Proteins—Roles in Reproduction, Cancer, and Immune Defense

“…In addition to increased rates of apoptosis, decreased tumor progression after virally mediated delivery in vivo appeared to depend, at least in part, on antiangiogenic and immunostimulatory activities (259). The preimmunization of mice with a Glipr1-modified tumor cell vaccine was also partially protective against the development of prostate cancer in an orthotopic cancer model (260), and, perhaps most compellingly, mice lacking Glipr1 had a significantly increased predisposition to spontaneous tumor growth when compared with wild-type littermates (261). It is also of note that Glipr heterozygous animals were significantly more disposed to developing tumors than wild-type animals, suggesting that the proapoptotic effect of GLIPR1 is stochastic in nature (261).…”

Identification of GLIPR1 tumor suppressor as methylation-silenced gene in acute myeloid leukemia by microarray analysis

“…It has been suggested that GLIPR1 plays a role in the immune surveillance (Szyperski et al 1998). Adenoviral vector-mediated delivery of mouse GLIPR1 into orthotopic mouse prostate cancer signiWcantly suppressed tumor growth and metastasis to lung (Satoh et al 2003), whereas administration of a mouse GLIPR1 gene modiWed tumor cell vaccine to mice had signiWcant antitumor activity in a pre-clinical model of recurrent prostate cancer (Naruishi et al 2006). These properties suggest that GLIPR1 is a tumor suppressor gene in prostate cancer and possibly in other malignancies.…”