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

Frederick F. Lang, Janet M. Bruner, Gregory N. Fuller, Kenneth Aldape, Michael D. Prados, Susan Chang, Mitchel S. Berger, Michael W. McDermott, Sandeep M. Kunwar, Larry R. Junck, William Chandler, James A. Zwiebel, Richard S. Kaplan, W.K. Alfred Yung

From the Departments of Neurosurgery, Pathology and Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Department of Neurosurgery, University of California, San Francisco, CA; Departments of Neuro-Oncology and Neurosurgery, University of Michigan, Ann Arbor, MI; North American Brain Tumor Consortium; Cancer Therapy Evaluation Program, Division of Cancer Therapy and Diagnosis, National Cancer Institute, Bethesda, MD; and Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD.

Address reprint requests to Frederick F. Lang, MD, Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 442, Houston, TX 77030-4009; email: flang{at}mdanderson.org.

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 p21^CIP/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.

Supported by National Cancer Institute grants CA62399 (to the North American Brain Tumor Consortium), CA62412, CA16672 (to The University of Texas M. D. Anderson Cancer Center), CA62422, MO1-RR00079 (to University of California, San Francisco), and MO1-RR00042 (to University of Michigan); and grants from the Anthony Bullock III Brain Tumor Research Fund and the Brian McCulloch Memorial Brain Tumor Fund (to F.F.L.).

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