Recombinant DNA Advisory Committee - 10/7-8/91 
indicate a clinical trial is a difficult one. The committee must determine the scientific 
merit of what is being proposed, and evaluate the safety for the patient and the public at 
large. This is a potentially new approach for treatment of human cancer, and it should 
move forward rapidly. This approach should encompass both dimensions, the pursuit of 
animal studies and the treatment of patients. 
Dr. Haselkorn asked about the intent of the investigators' use of the term "vaccine" in 
the description of the proposed therapy. Dr. McCune said the definition of vaccine in 
the dictionary is very broad. Vaccine refers to any approach by which the progress of a 
disease is impeded. Dr. Geiduschek said the phrase "by inoculation" is part of the 
definition. It is indeed broad, and it represents a process that was developed long before 
an understanding of immunology. 
Dr. McCune said there are two mechanisms by which the therapy may work. One 
involves the local effects of the TK+ cells. The second is the contribution of the 
immune response as illustrated in the experiments using immunodeficient animals in 
which the unmodified, neighboring cells were not killed. In a broad sense, the therapy 
consists of the injection of an agent to produce a resistance to the disease in the patient. 
Dr. Haselkorn said that in the public's mind, there is a distinction between prospective 
and retrospective aspects of vaccination, which are confused in the protocol's 
nomenclature. 
Dr. Freeman said that in an effort to determine if this treatment will be safe for patients, 
an experiment was performed in which irradiated TK+ cells and non-irradiated TK+ 
cells were assayed for their effects on neighboring TK- cells. If the TK+ cells were 
irradiated and exposed to ganciclovir, they were killed. In in vitro mixing experiments, 
murine fibrosarcoma cells were mixed with human irradiated TK- cells or human 
irradiated TK+ cells. Adding between 10-50% irradiated cells could affect the 
neighboring TK- cells. Clearly, irradiating the tumor cells prior to administration would 
improve safety. In animal model experiments, the murine TK- cells were injected 
intraperitoneally on day zero. On day one either irradiated murine TK- cells or 
irradiated murine TK+ cells were injected intraperitoneally into the mice in a 50:1 ratio. 
Survival was prolonged as in previous experiments. The intraperitoneal injection of 
human TK+ cells into a mouse that had received a prior intraperitoneal injection of 
tumor cells at a 50:1 ratio, also provided prolonged survival. He reminded the 
committee that animals may die because of the subcutaneous tumor growing at the site 
of the needle track as a result of the injection of tumor cells at day zero. These tumor 
cells have not been exposed to the intraperitoneally injected TK+ cells. 
Dr. Leventhal asked about the status of the peritoneal cavity at the time of post-mortem. 
Dr. Freeman said he did not know because he had not performed autopsies on the dead 
animals. Dr. Leventhal asked if the experiments are limited to female mice. Dr. 
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Recombinant DNA Research, Volume 15 
