Recombinant DNA Advisory Committee- 9/12-13/94 
Drs. Jeffrey Holt and Carlos B. Arteaga of the Vanderbilt University, Nashville, 
Tennessee, may conduct gene transfer experiments on 10 female patients (over 18 years of 
age) with metastatic breast cancer. Parent effusions from pleura or peritoneum will be 
drained and the fluid will be replaced with a supernatant containing retroviral vectors. 
The retroviral vectors, XM6:antimyc and XM6:antifos, are constructed with the N2 murine 
retroviral vector to express antisense sequences of c -myc and c-fos under the control of a 
mouse mammary tumor virus promoter. The vectors are designed for expression in breast 
cells. The primary endpoints are: (1) to assess uptake and expression of vector sequences 
in breast cancer cells of pleural and peritoneal fluids and to determine if the expression is 
specific to breast cancer cells; (2) to determine if viremia occurs following vector infusion; 
(3) to assess the local toxicity of vector infusion; and (4) to assess any reduction of 
malignant cells in pleural or peritoneal fluids. 
IX. ADDITION TO APPENDIX D OF THE NIH GUIDELINES REGARDING A HUMAN 
GENE TRANSFER PROTOCOL ENTITLED: EVALUATION OF REPEAT 
ADMINISTRATION OF A REPLICATION DEFICIENT, RECOMBINANT 
ADENOVIRUS CONTAINING THE NORMAL CYSTIC FIBROSIS TRANSMEMBRANE 
CONDUCTANCE REGULATOR cDNA TO THE AIRWAYS OF INDIVIDUALS WITH 
CYSTIC FIBROSIS /DYL CRYSTAL 
Review--Dr. D. Ginsburg 
Dr. Walters welcomed Dr. Harold Ginsberg, an ad hoc consultant on adenovirus vectors, 
to the meeting. 
Dr. Walters then called on Dr. D. Ginsburg to present his primary review of the protocol 
submitted by Dr. Ronald G. Crystal of New York Hospital-Cornell Medical Center, New 
York, New York. Dr. D. Ginsburg said that this is the first protocol that he has reviewed 
for the RAC. This study is to treat CF with an adenovirus expressing the CFTR gene. 
The main differences from Dr. Crystal’s previous study involve a change of the adenovirus 
vector with a cytomegalovirus (CMV) promoter and a test of escalating repeat doses of 
vector administration. Dr. D. Ginsburg said that these investigators are highly qualified 
with considerable expertise in the use of adenovirus vectors to treat CF patients. There 
are 3 distinct parts of the protocol involving a total of 26 patients. In Part A, escalating 
doses of adenovirus vector will be administered to 3 sites in large airways of the same 
lung. Two patients will be treated at each dosage level, beginning with 2 x 10 6 plaque 
forming units (pfu) per site and increasing to 2 x 10 9 pfu per site, for a total of 14 patients. 
In Part B, an additional 12 patients will be studied in 3 groups with the dose and schedule 
of repeat administration determined from the results of the first part of the study. In Part 
C, the same patients as in Part A will receive a repeat dose at a 10-fold higher level on 
days 90 and 180. In all patients, safety and CFTR expression will be monitored. The 
aims of this study are to examine the effect of more localized vector administration and to 
determine the responses to repeated treatment and increasing vector dosage. 
Dr. Crystal provided a preprint of a manuscript in press for publication describing results 
of his previous study. Dr. D. Ginsburg was pleased to see the published work. He raised 
Recombinant DNA Research, Volume 20 
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