Recombinant DNA Advisory Committee - 6/9-10/94 
12 transduced cells resulted in regression of contralateral tumors. Systemic IL-12 toxicity 
data demonstrated tumor regression 28 days following inoculation of the primary tumors. 
The proposed starting dose for the human protocol is 10 ng IL- 12/24 hours. This dose is 
l/70th the dose used for the murine systemic administration studies. In primates, the 
maximum tolerated dose of EL- 12 is as high as 1 mg/kg body weight. Dr. Parkman said 
the safety margin represented by these recent studies is more than adequate. However, 
the RACs concerns about the nature of the vector remain to be resolved. 
Review~Ms. Meyers (presented by Dr. Walters) 
Dr. Walters summarized the written comments submitted by Ms. Meyers. Ms. Meyers 
noted that the types of cancer proposed for treatment and the number of patients are 
not clearly stated in the protocol. Will the maximum number of subjects entered on the 
study be 18 or 43? Ms. Meyers suggested that Informed Consent issues, i.e., costs for 
non-negligent injuries, alternative therapies, life-long follow-up, contraception, and 
autopsy should be clearly described. 
Other Comments 
Dr. Parkman inquired about the exact vector that will be used for the human study. He 
agreed with Dr. Miller's comments that the issue of vector rearrangement should be 
addressed. Dr. Chase inquired about the rationale for testing a broad range of 
interleukin cytokines. Does the adoptive transfer of cytokine-producing cells hold 
promise for the treatment of cancer? Discussion ensued about the use of cytokines for 
the treatment of cancer. The consensus of the RAC was that this area of research may 
be beneficial based on preclinical data; therefore, human studies are of value. 
Dr. Zallen agreed with the comments submitted by Ms. Meyers noting that the 
description of the murine virus should be revised such that it is more understandable to 
laypersons. 
Investigator Response-Dr. Lotze 
Dr. Lotze explained that the terms TFG-IL-12 and TFG-ED12-Neo are used 
interchangeably. The vector is derived from the MFG vector that was made by Dr. 
Richard Mulligan of the Whitehead Institute, Cambridge, Massachusetts. MFG was 
designed for a single gene insert, whereas, DFG is for a double gene insert. The vector 
construct encodes the genes for the p35 and p40 subunits of IL-12. TFG refers to the 
DFG construct with the addition of neo^. 
With regard to Dr. Miller's question regarding the vector structure. Dr. Lotze explained 
that neo^ was placed between the p35 and p40 subunit genes to prevent splicing out of 
neo^ following selection of transduced cells in G418. Southern blot analysis confirms the 
structure of the vector DNA in the transduced cells. This construct has two identical 600 
base pair IRES elements for internal initiation of protein synthesis. There was concern 
that homologous recombination of these elements would splice out the middle portion of 
[360] 
Recombinant DNA Research, Volume 19 
