Recombinant DNA Advisory Committee - 2/10-11/92 
resubmitted by the investigators. The RAC requested that Dr. Freeman perform extensive 
analysis of the underlying principles of the proposed therapies. The basic biological 
premise for this protocol has not even been addressed. In addition, the 
immunotherapeutic aspects of the protocol are insufficiently described. 
Presentation-Dr. McCune 
Dr. McCune stated that the investigators are proposing to transfer the TK gene into 
cultured ovarian tumor cells. These cells will be irradiated to inhibit cell division and 
injected intraperitoneally. Ganciclovir will then be administered to the patients, 
specifically killing the HSV-TK( + ) cells as well as neighboring cells. 
Dr. McCune explained that the animal models show only a modest prolongation of life; 
the real goal is a cure. There are two types of prophylactic experiments using a mammary 
adenocarcinoma tumor. In the first experiment, mice were immunized with irradiated 
tumor cells and an adjuvant, C. parvum , before challenge with subcutaneous tumor. In the 
control group, which received no vaccination, the mice died in three to four weeks. In the 
mice that received irradiated tumor cells and the bacterial adjuvant, 10 of 15 animals 
remained disease-free and never developed tumors. To more closely mimic the human 
scenario, irradiated cells were injected after the tumor had developed. In this therapeutic 
model, the mice were challenged with intraperitoneal tumor before administration of 
irradiated cells. This model was not successful because mice require 10 to 14 days to 
recognize a foreign antigen. The tumor cells proliferated too quickly to be affected by the 
treatment. An attempt was made to slow down the progression of the tumor by injecting 
the tumor cells into the leg instead of the abdomen. This subcutaneous tumor was 
subsequently irradiated and a 50% cure rate was observed. 
Dr. McCune described a study in which cultured ovarian cancer cells had been infected 
with influenza virus and then lysed. This material was then injected intraperitoneally. 
Nine of 40 patients had a measurable response to the treatment. 
Dr. McCune stated that the proposed therapeutic effect cannot be well demonstrated in 
animal models because of the time that is required to immunize them. However, if 
prolongation of survival is demonstrated, this result should provide justification of the 
treatment. As for the mechanism of action. Dr. McCune said that sufficient data had been 
submitted to demonstrate that apoptotic vesicles could transfer phosphorylated ganciclovir 
to neighboring cells. However, the immune system aspects of the therapy are difficult to 
address. Hopefully, understanding the mechanism of action will not be a rigid criterion for 
approval. 
Dr. Freeman stated that the protocol is designed to treat patients with ovarian cancer 
Recombinant DNA Research, Volume 15 
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