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Conrad Notes
a timely medical meeting newsletter
GENE REPLACEMENT THERAPY (GPR)
S. Swisher, MD, The University of Texas M.D. Anderson Cancer Center, Houston, Tex, presented Phase I results after injecting tumors with normal p53 genes carried by a noncommon cold adenovirus. Normal p53 genes replaced the mutated form judged responsible for the unchecked cell division in the advanced nonsmall cell lung cancer (NSCLC) patients. Encouraging results followed 6 months' treatment with GPR alone and premedication with cisplatin (CDDP).

Rationale for GPRNormally, tumor suppressor genes such as p53 regulate cell growth and division. The most commonly found mutated gene in human cancer is p53, according to J.A. Roth, MD, a colleague of Swisher's. Abnormal p53 genes no longer stop cell division or hasten cell death and lead to cancer.

Replacing the abnormal p53 gene needs a carrier to enter the cancer cell. The transport mechanism in this study consists of noninfectious adenovirus. It brings normal p53 genes directly into cancer cells to replace abnormal p53 genes.

Procedure in NSCLC Eleven NSCLC patients received escalating doses of adenoviral p53 as monthly intratumor injections for 6 months. Ten others, pretreated 3 days prior with intravenous CDDP at 80 mg/m sq also received adenoviral p53. Standard Phase I safety monitoring ensued with monthly abdominal and chest CT scans. Immunochemistry testing of lung biopsy samples preceded and followed injection of adenoviral p53.
Results on 20 patients Anti-adenoviral antibodies developed in all patients after 6 injections. Some patients showed a transient fever but none experienced anaphylaxis. Side effects did not worsen with CDDP comedication.

At 5.5 months follow-up, the 11 patients treated with adenoviral p53 alone showed partial response, 1/11, stable disease, 5/11, and progressive disease, 5/11. Addition of CDDP in 10 others proved more promising in 9 evaluable patients: partial response, 1/9, stable disease, 8/9, and progressive disease, 0/9. Also, combined treatment with adenoviral p53 and CDDP decreased the median time to progression of the injected lesion by 37% compared with adenoviral p53 alone.

Injected adenoviral p53 monotherapy produced a dose-related tumor response. Six patients treated with 108 or 109 plaque forming units (pfu) showed partial response, 1/6, stable disease, 4/6, and progressive disease, 1/6. Lower doses such as 106 or 107 pfu in 5 other patients led to stable disease in 1/5 and progressive disease in 4/5.

Comments The results of this study are encouraging but require cautious interpretation in view of the small number of patients and short observation period. The investigators plan to start a Phase II study to further evaluate the safety and efficacy of adenoviral p53 in NSCLC patients.

For professional correspondence, please contact Dr. Swisher at: sswisher@surg.mdacc.tmc.edu

Eugene A. Conrad

Presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO) on May 17-20, 1997
CONRAD NOTES, © 1997 All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078 / June 1997

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