Recombinant DNA Advisory Committee - 12/1-2/94 
Dr. Par km an presented Dr. Motulsky’s written comments. Dr. Motulsky states that the investigators are using 
a biologically plausible gene therapy approach for cancer therapy yet they do not define the exact nature of the 
head and neck tumors to be studied. The exact type and extent of the tumors to be treated should be 
thoroughly defined. Dr. Parkman stated that the other issues raised in Dr. Motulsky’s written review have 
been previously addressed. 
Other Comments 
Dr. Brinckerhoff asked the investigators to comment on the possible immune reactions that could occur in 
response to these murine cells. VPC injection into head and neck tumors is very different than administering 
these cells in brain tumors which are insulated by the blood brain barrier. The proposed study could induce 
serious humoral and/or cellular immune responses and anaphylaxis. Dr. Parkman remarked that even for the 
brain tumor protocols, inflammatory response in the closed brain space could be serious; however, sometimes 
the inflammatory responses against the tumors are beneficial to the therapy. The special concern for the head 
and neck is that a local edema can sometimes be a serious problem. Dr. Parkman suggested that a skin test 
should be performed to determine the possibility of a delayed hypersensitivity reaction in patients. Dr. 
Brinckerhoff agreed that such a skin test would provide a beneficial screen for hypersensitivity. 
Dr. Miller questioned the persistence of VPC in head and neck tumors. Will VPC persist long enough in situ 
to secrete enough vector to transduce the tumor cells? The injected VPC might be immediately lysed by 
human complement. He explained that complement lysis was less of a concern for the brain tumor studies 
since there is a low complement level in cerebral spinal fluid. Many studies suggest that VPC are lysed 
immediately in peripheral tissue. Dr. Miller commented that the rat is not a valid animal model for evaluating 
complement activity since rat complement does not lyse murine VPC. An appropriate model for complement 
gctivity would be a larger animal, i.e., a canine or primate model. The investigators should study the 
persistence of VPC in human tumors. 
Ms. Meyers asked for clarification regarding the antitumor effects observed with GCV alone. She inquired 
whether the antitumor responses observed in other studies could be attributable to GCV alone. Drs. Parkman 
and Smith noted that these GCV effects have not been observed in the HSV-TK/VPC brain tumor studies. 
These effects have been only observed in the preclinical human squamous cell/nude mice studies. 
Dr. Miller asked the investigators to clarify the difference between this modified vector and the previously 
approved vectors. 
Investigator Response-Dr. Gluckman 
Dr. Gluckman stated he would address the clinical and Informed Consent issues, and that Drs. Peter 
Stambrook (University of Cincinnati) and Chiang would respond to vector related issues. 
Dr. Gluckman explained that the majority of head and neck tumors involve squamous cell carcinoma that 
arises from the mucosa of the upper digestive tract, i.e., cancer of the mouth, tongue, pharynx, larynx, and the 
cervical esophagus. When these tumors are diagnosed early, current therapies may be effective; if tumors are 
presented at later stages, treatment is extremely difficult and requires extensive surgery in combination with 
radiation therapy. There is about 50% recurrence rate, and recurrent tumors usually occur locally, causing 
tremendous problems in the head and neck areas. These patients have no other alternative therapy. Since 
recurrence usually occurs locally, the tumors are easily accessible for evaluation and treatment, which may 
offer an advantage to the proposed gene therapy approach. MRI, CT scans, and ultrasonography can be 
effectively utilized to guide VPC injection and monitor antitumor response. The toxicity associated with the 
HSV-TK/VPC brain tumor protocols is related to cerebrospinal fluid circulation and will not be a problem for 
head and neck tumors. Since the majority of these patients have tracheostomy and gastrostomy, any potential 
complications due to local edema can be safely corrected. He noted that the Informed Consent document has 
been revised in response to the primary reviewers’ recommendations and approved by the IRB. 
Recombinant DNA Research, Volume 20 
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