Phase I Trial of Adenovirus-Mediated p53 Gene Therapy for Recurrent Glioma: Biological and Clinical Results

2003 ◽  
Vol 21 (13) ◽  
pp. 2508-2518 ◽  
Author(s):  
Frederick F. Lang ◽  
Janet M. Bruner ◽  
Gregory N. Fuller ◽  
Kenneth Aldape ◽  
Michael D. Prados ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Phase I ◽  
Injection Site ◽  
P53 Protein ◽  
Tumor Biology ◽  
P53 Gene ◽  
Maximum Tolerated Dose ◽  
Intratumoral Injection ◽  
En Bloc ◽  
Clinical Toxicity

Purpose: Advances in brain tumor biology indicate that transfer of p53 is an alternative therapy for human gliomas. Consequently, we undertook a phase I clinical trial of p53 gene therapy using an adenovirus vector (Ad-p53, INGN 201). Materials and Methods: To obtain molecular information regarding the transfer and distribution of exogenous p53 into gliomas after intratumoral injection and to determine the toxicity of intracerebrally injected Ad-p53, patients underwent a two-stage approach. In stage 1, Ad-p53 was stereotactically injected intratumorally via an implanted catheter. In stage 2, the tumor-catheter was resected en bloc, and the postresection cavity was treated with Ad-p53. This protocol provided intact Ad-p53–treated biologic specimens that could be analyzed for molecular end points, and because the resection cavity itself was injected with Ad-p53, patients could be observed for clinical toxicity. Results: Of fifteen patients enrolled, twelve underwent both treatment stages. In all patients, exogenous p53 protein was detected within the nuclei of astrocytic tumor cells. Exogenous p53 transactivated p21CIP/WAF and induced apoptosis. However, transfected cells resided on average within 5 mm of the injection site. Clinical toxicity was minimal and a maximum-tolerated dose was not reached. Although anti-adenovirus type 5 (Ad5) titers increased in most patients, there was no evidence of systemic viral dissemination. Conclusion: Intratumoral injection of Ad-p53 allowed for exogenous transfer of the p53 gene and expression of functional p53 protein. However, at the dose and schedule evaluated, transduced cells were only found within a short distance of the injection site. Although toxicity was minimal, widespread distribution of this agent remains a significant goal.

scholarly journals p53 gene therapy for non-small cell lung cancer: a preliminary report of phase I trial

2000 ◽  
Vol 82 ◽  
pp. 36
Author(s):  
Toshivoshi Fujiwara ◽  
Masafumi Kataoka ◽  
Atsushi Nakamura ◽  
Noriaki Tanaka
Keyword(s):  
Lung Cancer ◽  
Gene Therapy ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Preliminary Report ◽  
Phase I Trial ◽  
P53 Gene ◽  
Small Cell ◽  
Small Cell Lung

scholarly journals Phase I Study of Adenovirus p53 Administered by Bronchoalveolar Lavage in Patients With Bronchioloalveolar Cell Lung Carcinoma: ECOG 6597

2008 ◽  
Vol 26 (25) ◽  
pp. 4166-4171 ◽  
Author(s):  
Vicki Keedy ◽  
Wei Wang ◽  
Joan Schiller ◽  
Sunil Chada ◽  
Bonnie Slovis ◽  
...  
Keyword(s):  
Bronchoalveolar Lavage ◽  
Phase I ◽  
Lung Carcinoma ◽  
Adenovirus Vector ◽  
P53 Gene ◽  
Maximum Tolerated Dose ◽  
Symptomatic Improvement ◽  
Low Grade ◽  
Cell Lung Carcinoma ◽  
Best Response

Purpose This pilot phase I trial evaluated the safety and maximum-tolerated dose of p53 gene transfer using an adenovirus vector (Ad-p53) delivered via bronchoalveolar lavage (BAL) to patients with bronchioloalveolar lung carcinoma (BAC). Patients and Methods Patients were initially administered two treatments of Ad-p53 to a single involved lobe, beginning at 2 × 109 viral particles (vp) per dose and escalated to a maximum of 2 × 1012 vp. If a clinical benefit was seen and the treatment was well tolerated, additional doses could be administered to additional lobes. Results Twenty-five patients were treated at doses between 2 × 109 and 2 × 1012 vp. At 2 × 1012 vp, one patient experienced grade 4 pulmonary toxicity, and one patient died 25 days after his second cycle; therefore, a cohort of 10 patients was treated at the recommended phase II dose of 5 × 1011 vp, with no grade 4 toxicity observed. The most frequent toxicities included low-grade fever, hypoxia, and dyspnea. Of the 23 assessable patients, 16 had stable disease as their best response. Subjective improvement in breathing was noted in eight patients. Limited distribution of vector was observed, with transient detection in patient sputum for 1 to 2 days after administration. Conclusion Ad-p53 can be administered safely by BAL at 5 × 1011 vp with repeated dosing. Stabilization of disease and symptomatic improvement may warrant further studies of Ad-p53 or other adenoviruses administered by BAL in patients with BAC.

scholarly journals P53 gene: major mutations in neoplasias and anticancer gene therapy

2012 ◽  
Vol 42 (5) ◽  
pp. 845-853 ◽  
Author(s):  
Caroline Rocha de Oliveira Lima ◽  
Rogério Elias Rabelo ◽  
Valcinir Aloísio Scalla Vulcani ◽  
Lorena Damasio Cardoso ◽  
Nicaelle Luan de Moura Sousa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Gene Therapy ◽  
Molecular Weight ◽  
Cell Death ◽  
P53 Protein ◽  
Cell Cycle Control ◽  
P53 Gene ◽  
Neoplastic Transformation ◽  
Functional Aspects

The p53 gene encodes a protein that has molecular weight of 53kD and is also called p53 protein, being constantly studied for its classic concept of "genome guardian". This gene plays a range of essential functions to ensure the cell cycle control, in addition to playing a central role in carcinogenesis. With respect to neoplasias, it prevents the neoplastic transformation through three intricate mechanisms. Depending on the extent of the mutation, different responses may be sent by p53 and those range since the disruption of the cell cycle, the correction of the mutation through the activation of repair proteins or still, the induction of senescence or cell death by apoptosis. This review aims to address the structural and functional aspects of the p53 gene and protein, and also reaffirm their participation in the carcinogenesis control, approaching their major mutations and the anticancer gene therapy involving this gene.

scholarly journals Immunohistochemical Detection of Tumor Suppressor Gene p53 Protein in Feline Injection Site-associated Sarcomas

2001 ◽  
Vol 38 (2) ◽  
pp. 236-238 ◽  
Author(s):  
P. R. Nambiar ◽  
M. L. Jackson ◽  
J. A. Ellis ◽  
B. J. Chelack ◽  
B. A. Kidney ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Cell ◽  
Injection Site ◽  
Tumor Suppressor Gene ◽  
P53 Protein ◽  
P53 Gene ◽  
Suppressor Gene ◽  
Immunohistochemical Detection ◽  
Cell Nuclei ◽  
P53 Tumor Suppressor Gene

Sarcomas associated with injection sites are a rare but important problem in cats. Immunohistochemical detection of p53 protein may correlate to mutation of the p53 tumor suppressor gene, a gene known to be important in oncogenesis. The expression of nuclear p53 protein in 40 feline injection site-assocated sarcomas was examined by immunohistochemical staining. In 42.5% (17/40), tumor cell nuclei were stained darkly; in 20% (8/40), tumor cell nuclei were stained palely; and in 37.5% (15/40), tumor cell nuclei were unstained. Immunohistochemical detection of p53 protein in a proportion of injection site-associated sarcomas suggests that mutation of the p53 gene may play a role in the pathogenesis of these tumors.

scholarly journals Phase I/II adenoviral p53 gene therapy for chemoradiation resistant advanced esophageal squamous cell carcinoma

2006 ◽  
Vol 97 (6) ◽  
pp. 554-561 ◽  
Author(s):  
Hideaki Shimada ◽  
Hisahiro Matsubara ◽  
Tooru Shiratori ◽  
Takanori Shimizu ◽  
Shinichi Miyazaki ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Phase I ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
P53 Gene

scholarly journals Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma

2018 ◽  
Vol 36 (14) ◽  
pp. 1419-1427 ◽  
Author(s):  
Frederick F. Lang ◽  
Charles Conrad ◽  
Candelaria Gomez-Manzano ◽  
W.K. Alfred Yung ◽  
Raymond Sawaya ◽  
...  
Keyword(s):  
Phase I ◽  
Malignant Glioma ◽  
Intratumoral Injection ◽  
Oncolytic Adenovirus ◽  
Post Treatment ◽  
Recurrent Malignant Glioma ◽  
En Bloc ◽  
Term Survival ◽  
Group A ◽  
Group B

Purpose DNX-2401 (Delta-24-RGD; tasadenoturev) is a tumor-selective, replication-competent oncolytic adenovirus. Preclinical studies demonstrated antiglioma efficacy, but the effects and mechanisms of action have not been evaluated in patients. Methods A phase I, dose-escalation, biologic-end-point clinical trial of DNX-2401 was conducted in 37 patients with recurrent malignant glioma. Patients received a single intratumoral injection of DNX-2401 into biopsy-confirmed recurrent tumor to evaluate safety and response across eight dose levels (group A). To investigate the mechanism of action, a second group of patients (group B) underwent intratumoral injection through a permanently implanted catheter, followed 14 days later by en bloc resection to acquire post-treatment specimens. Results In group A (n = 25), 20% of patients survived > 3 years from treatment, and three patients had a ≥ 95% reduction in the enhancing tumor (12%), with all three of these dramatic responses resulting in > 3 years of progression-free survival from the time of treatment. Analyses of post-treatment surgical specimens (group B, n = 12) showed that DNX-2401 replicates and spreads within the tumor, documenting direct virus-induced oncolysis in patients. In addition to radiographic signs of inflammation, histopathologic examination of immune markers in post-treatment specimens showed tumor infiltration by CD8+ and T-bet+ cells, and transmembrane immunoglobulin mucin-3 downregulation after treatment. Analyses of patient-derived cell lines for damage-associated molecular patterns revealed induction of immunogenic cell death in tumor cells after DNX-2401 administration. Conclusion Treatment with DNX-2401 resulted in dramatic responses with long-term survival in recurrent high-grade gliomas that are probably due to direct oncolytic effects of the virus followed by elicitation of an immune-mediated antiglioma response.

Phase I Trial of Intraperitoneal Injection of the E1B-55-kd-Gene–Deleted Adenovirus ONYX-015 (dl1520) Given on Days 1 Through 5 Every 3 Weeks in Patients With Recurrent/Refractory Epithelial Ovarian Cancer

2002 ◽  
Vol 20 (6) ◽  
pp. 1562-1569 ◽  
Author(s):  
P. A. Vasey ◽  
L. N. Shulman ◽  
S. Campos ◽  
J. Davis ◽  
M. Gore ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Abdominal Pain ◽  
Phase I ◽  
Neutralizing Antibodies ◽  
Phase I Trial ◽  
P53 Gene ◽  
Recurrent Ovarian Cancer ◽  
Maximum Tolerated Dose ◽  
Clear Cut ◽  
Grade 3

PURPOSE: Resistance to chemotherapy in ovarian cancer is frequently associated with mutations in the p53 gene. The adenovirus dl1520 (ONYX-015) with the E1B 55-kd gene deleted, allowing selective replication in and lysis of p53-deficient tumor cells, has shown preclinical efficacy against p53-deficient nude mouse-human ovarian carcinomatosis xenografts. PATIENTS AND METHODS: We undertook a phase I trial of intraperitoneal dl1520 in patients with recurrent ovarian cancer. Sixteen women with recurrent/refractory ovarian cancer received 35 cycles (median, two cycles) of dl1520 delivered on days 1 through 5 in four dose cohorts: 1 × 109 plaque forming units (pfu), 1 × 1010 pfu, 3 × 1010 pfu, and 1 × 1011 pfu. RESULTS: The most common significant toxicities related to virus administration were flu-like symptoms, emesis, and abdominal pain. One patient receiving 1 × 1010 pfu developed common toxicity criteria grade 3 abdominal pain and diarrhea, which was dose-limiting. The maximum-tolerated dose was not reached at 1011 pfu, and at this dose level patients did not experience significant toxicity. There was no clear-cut evidence of clinical or radiologic response in any patient. Blood samples were taken for adenovirus DNA and neutralizing antibodies. Polymerase chain reaction data indicating presence of virus up to 10 days after the final (day 5) infusion of dl1520 are suggestive of continuing viral replication. CONCLUSION: This article therefore describes the first clinical experience with the intraperitoneal delivery of any replication-competent/-selective virus in cancer patients.

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