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Executive Summary

The National Institutes of Health's Recombinant DNA Advisory Committee approved an intrathecal gene transfer protocol for leptomeningeal carcinomatosis sponsored by Genetic Therapy, Inc. at its Dec. 2-3 meeting by a vote of 13-1. The protocol was submitted by NIH researcher Edward Oldfield, MD, and NIH visiting researcher Zvi Ram, MD. Oldfield told the RAC that "probably the biggest problem with...gene therapy... is how do you distribute your genetic material." He explained that "in this study you can take advantage of the fact that the [cerebral spinal fluid] circulates along the brain, spinal cord and reaches every single cell of the leptomeninges," the covering of the brain and spinal cord. The planned 20-patient dose-escalation study "will evaluate the dynamics of retroviral vectors in the subarachnoid space, assess the safety of this approach and evaluate its potential antitumor efficacy," the study abstract states. The viral vector, derived from a murine leukemia virus, will be provided by GTI. The trial protocol notes that the vector is a "very close relative" to the vector first approved by the RAC in June 1992 for use in a GTI-sponsored study by NIH researchers including Oldfield and Ram of gene transfer in brain tumors ("The Pink Sheet" June 8, 1992, T&G-9). An interim look at the trial found that five of eight patients in the earlier trial showed some response to the procedure ("The Pink Sheet" Sept. 13, p. 13). As in the previous study, the vector-producing cell line will be injected into patients to transduce the HS-tk gene into tumor cells. Patients will then be treated with gancyclovir (Syntex' Cytovene) to kill cells expressing the HS-tk gene. In the new protocol, the vector-producing cells will be injected intrathecally. The committee discussed another trial employing GTI vectors, this one designed for patients with Fanconi anemia type C. RAC voted 14-0 with two abstentions to defer the protocol. The committee noted that the sponsors -- NIH investigators Johnson Liu, MD, and Neal Young, MD -- could submit the additional requested data without resubmitting the entire protocol; the principal request from the RAC was additional analyses of data in mice that were under way but not yet completed. The committee also raised concerns about the growth factors Liu and Young proposed to use ex vivo to stimulate the growth of peripheral blood progenitor cells taken from the patient. Specifically, RAC members cited a submission by NIH investigator Cynthia Dunbar, NM, stating that her gene transfer study "generated data that would suggest that stem cell factor could favor the growth of leukemic versus normal progenitors during ex vivo conditions." The RAC requested clarification of her report. RAC member Ira Carmen, PhD, University of Illinois, commended the protocol for having "an entirely new gene therapeutic thrust." Fanconi's anemia is a fatal genetic disesase that appears in childhood. Fanconi's anemia type C is a subset of the disease for which the gene has been isolated. The committee also cleared an extension of Viagene's protocol for its in vivo ImmunoTherapeutic (HIV-1 IIIBenv/rev retroviral vector). The purpose of the study, to be conducted by Richard Haubrich, MD, University of California at San Diego, is to evaluate the safety and immunological effects of the treatment in HIV-1 infected, asymptomatic individuals. The original protocol was approved by the RAC in June ("The Pink Sheet" June 14, p. 6); the second protocol modifies the inclusion criteria to allow potential effects on immune function and disease progression to be assessed more quickly. In addition, patients will be given a single dosage of the vector (10 cfu/ml) rather than escalating doses, and use of antiretrovirals will be allowed during the study. Among other protocols reviewed by RAC, a Vical-sponsored trial involving direct gene transfer into hepatic metastases for treatment of advanced colorectal cancer was approved.

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