Recombinant DNA Advisory Committee - 2/10-11/92 
Dr. Freeman responded that autopsies were conducted, and that there is evidence that 
these animals were dying from intraperitoneal tumors. Dr. Geiduschek said that this result 
would indicate that the apoptotic vesicles are attacking the tumor but not totally destroying 
it. Dr. Freeman agreed with that statement. In the preimmunized mice, very prolonged 
survivals were observed and that further studies designed to study dosage should be 
undertaken simultaneously. Dr. Geiduschek asked if experiments had been performed on 
nude mice to examine the effect of apoptotic vesicles in the peritoneum. Dr. Freeman 
said those experiments would be probably conducted in the future. At this point, the focus 
is on the effect of TK( + ) cells on TK(-) cells. 
Dr. Geiduschek referred to the use of word "vaccine" in the protocol. Dr. Freeman stated 
that in his opinion the killing of adjacent tumor cells could be described as a vaccine 
effect. 
Dr. Gellert queried if there is direct cell killing, then why is there no effect observed in 
nude mice that are not immunocompetent. Dr. Gellert then mentioned a variety of cell 
lines that were used in these studies leading to conflicting results. The most critical 
experiment was performed on a colon carcinoma cell line, not an ovarian cancer cell line. 
Immunological specificity is hard to analyze, and the results of these experiments are 
leading to two diametrically opposite directions. Dr. McCune responded that a major 
difference between mouse and human cancers is that nearly all animal tumors are highly 
immunogenic. The immunogenic effect will require a few weeks to register its full effect; 
as a part of the acute reaction, the local inflammatory response from the apoptotic cells is 
probably what is killing the tumor cells. 
Dr. Freeman then remarked that the investigators are seriously considering the RAC's 
concerns regarding the mechanism of killing. They have tried diligently to determine the 
mechanism, but have not been able to establish it. A definitive answer to this question 
could take years. Hopefully, the risk/benefit ratio and relative safety to the patient 
population would allow this new therapy to proceed. 
Committee motion 
Dr. Post moved for the approval of the protocol, and Mr. Barton seconded the motion. 
Dr. Mclvor asked if the cells were assayed for the presence of replication-competent virus 
following irradiation. Dr. Freeman responded that these tests have not been performed. 
Dr. Mclvor noted that irradiating cells may result in the release of endogenous retrovirus. 
Dr. Freeman agreed to include this assay in the safety tests. 
Dr. H. Miller urged the RAC to vote in favor of the motion. The FDA will review the 
protocol to verify that the standards have been followed for autologous and heterologous 
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