Recombinant DNA Advisory Committee - 12/2-3/93 
Dr. Chang responded to the RAC's questions about preclinical data and stated that his 
co-investigator, Dr. Kraus, will address the RACs questions about the proposed vector 
and transduction procedures. 
Responding to the comments raised by Dr. Geiduschek, Dr. Chang said that in their own 
interpretation, the animal data demonstrates increased immunogenicity in response to 
IL-4 transduced lymphocytes compared to untransduced cells. Similar results have been 
obtained using another IL-4 expressing vector construct. Dr. Chang stated that Dr. 
Geiduschek's comparison between IL-4 and BCG is not pertinent for this human trial 
because a different and a more potent bacterial adjuvant, C. parvum, was used for the 
murine studies. Although the response with IL-4 transduced cells was similar to results 
obtained with C. parvum , IL-4 transduced cells were more effective than untransduced 
tumor cells alone. The animal data demonstrated an antitumor response for established 
tumors. For this reason, the animal studies provide sufficient justification for the 
proposed human clinical trials. 
I 
In response to Dr. Geiduschek's questions about immunological assays, Dr. Chang said 
that immune reactivity of draining lymph node cells will be determined by cytolytic 
activity, cell proliferation, and cytokine release. An autologous tumor cell delayed skin 
test will be used to determine the in vivo response. 
Dr. Parkman inquired about the number of animals used for the animal studies. Dr. 
Chang said that an extensive murine experiment was conducted involving 70 mice (5 
mice in each experimental group). This animal model is being used to define the most 
pertinent assays for the human study. 
f 
Dr. Geiduschek reiterated his reservations about the interpretation of the murine 
experiment. Since Dr. Chang has agreed that the experiment did not demonstrate an 
improved immune response using IL-4 transduced cells over the bacterial adjuvant, i.e., 
C. parvum , the animal data do not provide justification for the human study. Dr. 
Leventhal stated that the investigators should not be penalized for results that indicate 
that IL-4 therapy is equivalent to the best bacterial adjuvant therapy. Since IL-4 and 
BCG stimulate the immune system by different mechanisms, the combination of these 
two stimulants may yield a synergistic effect. Dr. Parkman cautioned that the animal 
data cannot be directly extrapolated to the human study. The relative potency of IL-4 
and bacterial adjuvants may be different in humans; however, it is unnecessary to 
demonstrate that IL-4 is a more effective stimulant to justify the human study. Patients 
should have the option to choose the clinical protocol in which they desire to participate. 
Dr. Leventhal added that BCG and C. parvum are very complex bacterial adjuvants, and 
IL-4 is a less complex protein; therefore, scientific interpretation of the IL-4 data would 
be less complicated. Dr. Chang presented additional murine data to substantiate his 
assertion that IL-4 transduced cells elicit an enhanced immunologic response as 
compared to untransduced cells. 
j 
Dr. Kraus answered the RACs questions about tumor cell transduction. Most of the 
experiments have been performed using late passage melanoma cells rather than early 
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Recombinant DNA Research, Volume 18 
