Recombinant DNA Advisory Committee - 3/3-4/94 
modification has been introduced at the splice acceptor site which permits expression of 
the transgene similar to the env gene mRNA of the Moloney murine leukemia virus. 
The investigators have demonstrated high level expression of the hybrid receptor gene in 
T cells. (3) Will the "ping-pong" method of cocultivation of ecotropic and amphotropic 
producer clones increase the probability of generating RCR? The investigators have 
supplied information regarding thorough RCR safety testing. (4) What will happen when 
large numbers of transduced T cells activated by viral proteins are infused into these 
HIV( + ) patients? The investigators have performed a murine experiment to evaluate 
this safety issue. A murine tumor cell line was engineered to express the HIV env gene, 
and transplanted in a nude mouse. The mouse was then infused with T cells transduced 
with the hybrid receptor gene. No serious toxicity was observed in the murine model. 
Dr. Post cautioned that the solid tumor model is very different from the human situation 
in which the HIV-infected cells are dispersed throughout the body. This safety issue is 
significant since the proposed initial cell dose is very high. (5) Will the transduced T 
cells be susceptible to HTV infection, therefore, expanding the number of HIV-infected 
cells in the body? The investigators submitted data demonstrating that the transduced 
cells are at least 1,000-fold less susceptible to viral infection compared to control 
CD4( + ) T cells. Dr. Post suggested that additional data using other clinical HIV isolates 
is preferable. (6) Will the CD4/C hybrid protein become immunogenic? The 
investigators responded that no immunological responses have been observed in HIV( + ) 
patients who received large quantities of soluble CD4 proteins. Dr. Post reconunended 
that patients should be monitored for anti-CD4 antibodies. 
Review-Dr. Carmen 
Dr. Carmen commented that the description of the proposed vector and its derivation 
are not understandable to laypersons because of the numerous undefined acronyms. He 
recommended specific changes to the Informed Consent document that would more 
clearly explain the vector and gene insert. As given, the description conveys little useful 
information to the research subject. 
Review— Dr. Brinckerhoff (presented by Dr. Post) 
Dr. Brinckerhoffs written comments raised several concerns. The proposed cell doses, 1 
X 10® and 1 x 10^° cells, represent an extremely large number of cells that could result in 
potential toxicity. How were the initial cell doses determined? The investigators' written 
response states that the proposed doses are within the range used for other adoptive 
immunotherapy protocols, e.g.. Dr. Rosenberg's (Protocol #9007-003) and Dr. 
Greenberg's (Protocol #9102-017). Will the hybrid receptor become antigenic? The 7- 
day experiment demonstrating the lack of transduced T cell infectivity by HIV is 
inadequate due to the insidious nature of HIV infection, the low level of T cell 
replication, and a relatively low multiplicity of infection in HIV patients. Is data 
available from the ongoing 14-day experiment? Efficacy will be difficult to demonstrate 
since the nature of HIV infection in insidious and variable. TTie investigators' written 
response states that the primary endpoint of this study is safety, not efficacy. 
[24] 
Recombinant DNA Research, Volume 19 
