Recombinant DNA Advisory Committee - 12/1-2/94 
The rate of integration may be low; therefore, an argument can be made that transformation of immune cells 
to IL-2 independent growth is unlikely, but presumably there will still be some risk. The possibility that gene 
transfer might result in uncontrolled cell growth was not a safety concern for the human leukocyte antigen-B7 
human gene transfer experiments. The supporting preclinical data is derived from short-term murine 
experiments. Long-term primate experiments would have been preferable to demonstrate safety. Dr. Miller 
said that the plasmid DNA poses little risk to others, but there could be some harm to patients in term of 
stimulation of T-cell growth in those patients. The safety issues need to be addressed in animals prior to use 
in humans. 
Review-Dr. Saha 
Dr. Saha said that this protocol is very similar to other RAC-approved protocols involving IL-2. One major 
difference is that the present study will utilize administration of IL-2 cDNA in liposomes without the benefit of 
a viral vector. One advantage of the proposed gene transfer method over viral vectors is that there is less 
likelihood of insertional mutagenesis. Liposome delivery is a less expensive means of gene transfer than viral 
delivery. There are no direct comparative studies of these two gene transfer methods. He said that most of 
his questions have been adequately answered in the investigators’ written responses. He strongly suggested 
that potential subjects should be encouraged to seek a second opinion regarding their options for further 
treatment before being enrolled in this protocol. He did not agree with the investigators’ written response that 
a second opinion is unnecessary because subjects will have failed all other available therapeutic options. Dr. 
Saha recommended approval of the study based on the life expectancy of the patient population and the 
precedent that has been set by approval of other IL-2 human gene transfer protocols. 
Other Comments 
Dr. Zallen commented that the investigators have provided adequate responses to Appendix M-I-D Informed 
Consent of the Points to Consider. She inquired about the limited amount of time in which subjects are 
required to make an informed decision about their participation in the study, i.e., 24 hours to 2 weeks. 
Dr. Parkman noted that the proposed study involves unspecified solid tumors and lymphomas. However, there 
is significant data in the literature that suggests that melanoma and renal cell carcinoma are more responsive 
to IL-2. Will the inclusion of numerous tumor types complicate the study design and a subsequent 
interpretation of data? Is there any evidence that IL-2 is effective in treating lymphoma? There are 
alternative therapies available for lymphoma, i.e., autologous bone marrow transplantation. 
Ms. Meyers thought that the Informed Consent document was very poorly written and should be revised. A 
request for autopsy should be included, and the patient responsibility for medical cost of untoward effects 
should be clearly disclosed. Mr. Capron agreed that the statements regarding medical costs are difficult to 
follow and should be clarified. Ms. Meyers stated that it is unacceptable to exclude patients from participation 
in the study who are unable to pay for such costs. Mr. Capron remarked that Phase I studies are not intended 
to benefit patients. 
Dr. Miller asked the investigators to clarify inconsistencies between the actual IL-2 sequence and the sequence 
that has been published in the literature. 
Investigator Response-Drs. Scheiber and Hersh 
Dr. Alan Scheiber (Vical, Inc.) responded to Dr. Miller’s concern about the safety of the IL-2 plasmid DNA. 
Dr. Scheiber said that in vitro transfection produces stable transfectants in fibroblasts at a frequency between 1 
and 5 x 10' 5 . Lymphocytes are more difficult to transfect by this liposome/DNA technique. Short-term murine 
safety studies of intravenous injections have been conducted. The primate study is still ongoing (Day 65 at the 
present time), and no hyperproliferation of T-cells has been observed. Dr. Miller said that T-cell transfection 
by IL-2 cDNA should be evident by Day 65. 
[456] 
Recombinant DNA Research, Volume 20 
