Human Gene Therapy Subcommittee - July 29-30, 1991 
over TK- cells was injected. This ratio would probably need to be reversed in patients. 
He requested additional data on the number of TK+ cells that are required to achieve 
ablation of the non-modified tumor cells. The protocol stated that autologous tumor 
cells are more effective than allogeneic tumor cells in prolonging patient survival. If 
this is the case, the patient's cells might be modified, obviating the need for the PA-1 
cell line. One mechanism of killing non-modified tumor cells is by metabolites of 
ganciclovir. Since this is the basis of traditional chemotherapy, a drug might be used to 
achieve the same effect. A better definition of expected effect is needed. Therefore, 
the principal concerns are the animal model, the vectors, and the rationale for the 
treatment. 
Dr. Kelley agreed with Dr. D. Miller a 50-fold excess of TK+ cells may not be feasible 
in the patients, and that the experiment may not work. Intraperitoneal levels of 
ganciclovir need to be quantitated. Patients should be selected based on expected 
survival. Patients entering into this protocol, should have the option to receive 
conventional therapies such as chemotherapy, radiation, and surgery, if deemed 
appropriate. 
Mr. Brewer said that the following areas in the consent form were not clearly defined: 
(1) the stopping rule, (2) patient selection criteria, and (3) the treatment procedures. 
Since additional clinical data must be collected following treatment, the patients should 
be informed that they may withdraw from the protocol at any time. In the section 
addressing costs associated with research injury, the consent form now states 
"compensation is not available for injury. This should be expanded to read "non- 
negligent injury". 
Dr. Leventhal expressed concern about patient eligibility. The protocol states that 
patients are initially in Stages I, II, or III. Patients should have clinical evidence of 
recurrent progressive or residual disease and not have nodules greater than 2 cm. It 
will be difficult to identify these patients by a physical exam or CT scan. Patients may 
not receive a laparotomy within three months prior to entering into the protocol. 
Therefore, it seems they would have to be followed by Ca^^ to diagnose tumor 
recurrence. The investigators need to clarify how they plan to make this assessment. 
Dr. Freeman responded by saying that in designing this study he sought to develop 
animal models that would address both safety and efficacy. The patient population will 
consist of Stages I, II, and III ovarian cancer patients who are in relapse and have only 
a minimal response to second-line chemotherapy. Selection criteria will specify that 
patients have no other alternative form of standard therapy available. The protocol is 
designed to genetically engineer tumor cells using retroviral vectors that contain 
negative selectable markers. Under appropriate conditions, these tumor cells can then 
be killed. The negative selectable marker to be used is the HSV-TK gene. When 
exposed to ganciclovir, the cells containing this gene will die. The goals are: (1) to 
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