Showing papers by "Robert L. Martuza published in 1999"
TL;DR: It is demonstrated that infection of established tumors with HSSV-1 mutant G207 also induces a highly specific systemic anti-tumor immune response, and intratumoral G207 inoculation is able to inhibit tumor growth both by local cytotoxic viral replication in tumor cells and induction of a systemicAnti-t tumour immune response.
Abstract: The success of cancer gene therapy is likely to require the targeting of multiple antitumor mechanisms. One strategy involves the use of attenuated, replication-competent virus vectors, such as herpes simplex virus type 1 (HSV-1) mutant G207, which is able to replicate in human tumor cells with resultant cell death and tumor growth inhibition, yet is nonpathogenic in normal tissue. In this study, we demonstrate that infection of established tumors with G207 also induces a highly specific systemic anti-tumor immune response. In a syngeneic, bilateral established subcutaneous tumor model, with mouse CT26 colorectal carcinoma cells in BALB/c mice or M3 melanoma cells in DBA/2 mice, unilateral intratumoral inoculation with G207 caused a significant reduction in the growth of both the inoculated and contralateral noninoculated tumors. This elicited anti-tumor response is dependent on viral infection of the tumor, as intradermal inoculation of G207 in BALB/c mice had no effect on CT26 tumor growth. Treatment of...
269 citations
TL;DR: The results suggest that the oncolytic antitumor action of replication-competent HSV may be augmented by induction of specific and systemic antitUMor immunity effective both in the periphery and in the brain.
Abstract: Replication-competent, attenuated herpes simplex virus (HSV) vectors have been developed for viral oncolytic therapy of primary and metastatic malignant brain tumors. However, the role of the host immune responses in the brain has not been elucidated. N18 neuroblastoma cells were used as a tumor model in syngeneic A/J mice to test the therapeutic efficacy of G207, a conditionally replicating HSV vector, in an immunocompetent condition. G207 inoculated intraneoplastically exhibited a prominent oncolytic antitumor effect in mice harboring N18 tumors in the brain or subcutaneously, and, in addition, elicited a systemic antitumor immune response. Subcutaneous tumor therapy with G207 caused regression of a remote, established tumor in the brain or in the periphery, which was potentially mediated by the systemic antitumor immune response, and provided persistent tumor-specific protection against N18 tumor rechallenge in the brain as well as in the periphery. Antitumor immunity was associated with an elevation of specific CTL activity against N18 tumor cells that persisted for at least 13 months. The results suggest that the oncolytic antitumor action of replication-competent HSV may be augmented by induction of specific and systemic antitumor immunity effective both in the periphery and in the brain.
215 citations
TL;DR: It is concluded that intracerebral inoculation of up to 109 PFU of G207, well above the efficacious dose in mouse tumor studies, is safe and therefore appropriate for human clinical trials.
Abstract: This study examined the safety of intracerebral inoculation of G207, an attenuated, replication-competent herpes simplex virus type 1 (HSV-1) recombinant, in nonhuman primates. Sixteen New World owl monkeys (Aotus nancymae [karyotype 1, formerly believed to be A. trivirgatus]), known for their exquisite susceptibility to HSV-1 infection, were evaluated. Thirteen underwent intracerebral inoculation with G207 at doses of 107 or 109 PFU, two were vehicle inoculated, and one served as an infected wild-type control and received 103 PFU of HSV-1 strain F. HSV-1 strain F caused rapid mortality and symptoms consistent with HSV encephalitis, including fever, hemiparesis, meningitis, and hemorrhage in the basal ganglia. One year after G207 inoculation, seven of the animals were alive and exhibited no evidence of clinical complications. Three deaths resulted from nonneurologic causes unrelated to HSV infection, and three animals were sacrificed for histopathologic examination. Two animals were reinoculated with G207 (107 PFU) at the same stereotactic coordinates 1 year after the initial G207 inoculation. These animals were alive and healthy 2 years after the second inoculation. Cerebral magnetic resonance imaging studies performed both before and after G207 inoculation failed to reveal radiographic evidence of HSV-related sequelae. Despite the lack of outwardly observable HSV pathology, measurable increases in serum anti-HSV titers were detected. Histopathological examination of multiple organ tissues found no evidence of HSV-induced histopathology or dissemination. We conclude that intracerebral inoculation of up to 109 PFU of G207, well above the efficacious dose in mouse tumor studies, is safe and therefore appropriate for human clinical trials.
185 citations
TL;DR: G207 is a multimutated herpes simplex virus 1 (HSV) vector that replicates within cancer cells, causing cellular death; however, replication is limited in normal cells, including those of the nervous system, and is oncolytic for multiple human prostate cancer cells.
Abstract: Prostate adenocarcinoma is the most common nonskin malignancy in males and the second most common cause of cancer death in the United States (Landis et al., 1998). Initial treatments of surgery or radiotherapy may cause impotence and/or incontinence from neural damage (Eastham and Scardino, 1998; Porter et al., 1998). When extraprostatic or metastatic disease develops, castration or pharmaceutical androgen ablation is utilized (Catalona, 1994). Androgen-resistant recurrence indicates a poor prognosis and justifies experimental chemotherapy (Oh and Kantoff, 1998). G207 (Mineta et al., 1995; Yazaki et al., 1995) is a multimutated herpes simplex virus 1 (HSV) vector that replicates within cancer cells, causing cellular death; however, replication is limited in normal cells, including those of the nervous system. In vitro, G207 at a low multiplicity of infection (MOI of 0.01) is oncolytic for multiple human prostate cancer cells. In athymic mice, a single intraneoplastic inoculation of G207 completely eradica...
160 citations
TL;DR: It is concluded that G207 should be considered for the treatment of head and neck cancer and that combination with chemotherapeutic agents may improve efficacy.
127 citations
TL;DR: It is concluded that HSV seropositivity should not deleteriously affect the efficacy of G207 tumor therapy, and multiple inoculations of virus should be considered for clinical evaluation.
Abstract: Replication-competent, attenuated mutants of herpes simplex virus type 1 (HSV-1) have been shown to be efficacious for tumor therapy However, these studies did not address the consequences of prior exposure to HSV, as will be the case with many patients likely to receive this therapy Two strains of mice, A/J and BALB/c, were infected with wild-type HSV-1 by intraperitoneal injection and the immune response was determined by plaque reduction assay for neutralizing antibody and ELISA for IgG and IgM Syngeneic tumors, N18 neuroblastoma and CT26 colon carcinoma, were implanted subcutaneously in HSV-1 seropositive and naive A/J and BALB/c mice, respectively Established tumors were subsequently treated intratumorally with a multi-mutated HSV-1, G207 G207 inhibited tumor growth to a similar extent whether the mice were seropositive or not We next examined the effect of multiple intratumoral inoculations of a 10-fold lower dose of G207 on tumor growth In the multiple treatment group (biweekly for 3 weeks), 75% of tumors were cured, whereas no cures were seen in the single treatment group We conclude that HSV seropositivity should not deleteriously affect the efficacy of G207 tumor therapy, and multiple inoculations of virus should be considered for clinical evaluation
97 citations
TL;DR: Recombinant HSV G92A regulated by the albumin enhancer/promoter inhibited the growth of established subcutaneous hepatoma tumors in nude mice, but not prostate tumors, suggestingReplication-competent viral vectors controlled by cell-specific transcriptional regulatory sequences provide a new therapeutic strategy for tumor therapy.
Abstract: Targeting viral vectors to appropriate cell types so that normal cells are not adversely affected is an important goal for gene therapy. Previously, we described a novel approach to viral gene therapy using a conditional, replication-competent herpes simplex virus (HSV), where replication and associated cytotoxicity are limited to a specific cell-type by the regulated expression of an essential immediate–early viral gene product. In this report we analyze the hepatoma-specific replication, cytotoxicity and anti-tumor effect of recombinant HSV G92A, regulated by the albumin enhancer/promoter. G92A efficiently replicated in vitro in two human hepatoma cell lines expressing albumin, but not in four human non-hepatoma, albumin-non- expressing tumor cell lines, while all cell lines were equally susceptible to a tissue nonspecific HSV recombinant, hrR3. In vivo, G92A replicated well in subcutaneous xenografts of human hepatoma cells (Hep3B) in athymic mice, but not in non-hepatoma subcutaneous tumors (PC3 and HeLa), whereas, hrR3 replicated well in both tumor types. Intratumoral inoculation of G92A inhibited the growth of established subcutaneous hepatoma tumors in nude mice, but not prostate tumors. Replication-competent viral vectors controlled by cell-specific transcriptional regulatory sequences provide a new therapeutic strategy for tumor therapy.
63 citations
TL;DR: Results indicate that the oncolytic activity of G207 is retained under corticosteroid administration, however, intensive immunosuppression may diminish the long-term efficacy of G 207 owing to suppression of tumor-specific cytotoxic T lymphocyte induction.
Abstract: A multimutated, conditionally replicating herpes simplex virus type 1, G207, has been developed as an effective means of treating human malignant brain tumors. We have shown that intraneoplastic inoculation of G207 induces a specific and systemic antitumor immune response that plays an important role in the antitumor activity, in addition to the direct oncolytic action of G207. Since a large number of malignant brain tumor patients are treated with corticosteroids, it is important to evaluate whether the therapeutic efficacy of G207 is affected by corticosteroid-induced immunosuppression. For a tumor model, we used G207-permissive N18 murine neuroblastoma cells implanted subcutaneously in syngeneic A/J mice. Intraneoplastic inoculation of G207 (107 PFU) induced significant suppression of tumor growth whether or not dexamethasone (5 mg/kg) was given. When dexamethasone was given for an extensive time (16 days starting on day - 2), all G207-treated mice showed tumor growth despite initial shrinkage, whereas...
57 citations
TL;DR: The skin is introduced as a source of dysregulated growth factors in neurofibromatosis type 1, and the further study of the angiogenic factor midkine is suggested in the pathogenesis of this common autosomal dominant disorder.
27 citations
Patent•
18 Nov 1999
TL;DR: A test for abnormal levels of midkine protein and/or the mRNA sequence that encodes the mid kine protein can be used to diagnose a neurofibromatosis type 1 disorder as discussed by the authors.
Abstract: Neurofibromatosis type 1 disorders result in abnormal levels of midkine protein and/or the mRNA sequence encoding the midkine protein in the skin and/or blood serum of individuals having the disorder Thus, test for abnormal levels of midkine protein and/or the mRNA sequence that encodes the midkine protein can be used to diagnose a neurofibromatosis type 1 disorder
4 citations