Recombinant DNA Advisory Committee - 12/2-3/93 
Dr. Walters called on Dr. Doi to present his primary review of the protocol submitted by 
Dr. Joseph Rubin of the Mayo Clinic, Rochester, Minnesota. Dr. Doi stated that the 
primary objective of this study is to determine the safety and feasibility of the direct 
injection of DNA/lipid complexes into hepatic metastases of patients with advanced 
colorectal carcinoma. This protocol is similar to Dr. Nabel's protocol that was previously 
approved by the RAC at its June 1993 meeting. There is no increased risk to patients in 
the present protocol, and the present approach is even more conservative than that of 
Nabel's. The investigators will attempt to stimulate an in vivo immune response by 
direct intratumoral injection of lipid complexes containing genes encoding the HLA-B7 
histocompatibility antigen and 6-2 microglobulin. In vivo data demonstrates the 
attenuation of tumor growth; and in some instances, complete tumor regression as a 
result of this treatment. The DNA of the plasmid vector, pHLA-B7/6-2, will be mixed 
with the cationic lipid, DMRIE (l,2-dimyristyloxypropyl-3-dimethylhydroxyethyl 
ammonium bromide), and the neutral lipid, DOPE (dioleoylphosphatidylethanolamine). 
These DNA/lipid complexes will be injected into the tumor by a thin needle guided by 
sonography. The procedure has an accuracy rate of 98%. The injection sites will be 
visualized and documented on videotape. Approximately 1% of cells within the tumor 
mass will be transfected. A total of 15 HLA-B7(-) colorectal patients with hepatic 
metastases will be treated in dose-escalation groups to determine toxicity. Patients will 
be divided into two treatment schedules. Toxicity symptoms such as fatigue, weight loss, 
nausea, vomiting, hemorrhage, infection, and liver chemistries will be evaluated during 
the test period and immunologic responses will be monitored. Most of the safety issues 
have been addressed. Although there is no control group in the present study and no 
clear description about the immune responses that will be monitored, Dr. Doi 
recommended approval of the protocol. 
Review-Dr. DeLeon 
Dr. DeLeon said that this protocol is a conservative revision of Dr. Nabel's previously 
approved protocol. She noted some inconsistency in the number of hepatic injections 
between the Informed Consent document and the protocol. However, the investigators 
have clarified this issue. A request for autopsy should be included in the Informed 
Consent document. Dr. DeLeon recommended approval of the protocol. 
Review-Mr. Capron (presented by Dr. DeLeon) 
Dr. DeLeon provided an overview of Mr. Capron's written review to the Informed 
Consent document. The term "therapy" should not be used because the investigational 
nature of the study is not adequately conveyed. Suggested language was submitted that 
would improve comprehension by laypersons. 
Other Comments 
Dr. Leventhal asked the investigators to compare the doses of DNA to those 
administered in Dr. Nabel's protocol. Ms. Meyers raised several concerns about the 
Informed Consent document, i.e., long-term follow-up, recommendations for 
Recombinant DNA Research, Volume 18 
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