Recombinant DNA Athnsory Committee - 3/3-4/94 
not continue on this study if an HLA match at any locus is not identified, and (4) a 
revised patient assent form written in language that is understandable to children. 
Dr. Walters noted that Dr. Parkman abstained from voting on this protocol since he is 
employed by the same institution as Dr. Seeger, the Children's Hospital, Los Angeles, 
California. 
VI. ADDITION TO APPENDIX D OF THE NIH GUIDELINES REGARDING A HUMAN 
GENE TRANSFER PROTOCOL ENTITLED; A PHASE //// PILOT STUDY OF THE 
SAFETY OF THE ADOPTIVE TRANSFER OF SYNGENEIC GENE-MODIFIED 
CYTOTOXIC T-LYMPHOCYTES IN HIV-INFECTED IDENTICAL TWINS /DR, 
WALKER 
Review-Dr. Post 
Dr. Walters called on Dr. Post to present his primary review of the protocol submitted 
by Dr. Robert E. Walker of the NIH, Bethesda, Maryland. Dr. Post said that this 
protocol is extremely innovative because of the novel function of the transferred gene; T 
cells will be activated when HIV antigens are encountered. Specifically, in response to 
the HIV envelope {env) protein. HIV infection progressively destroys the human 
immune system and ultimately results in acquired immunodeficiency syndrome (AIDS). 
CD8( + ) T cells kill virus infected cells. AIDS may result from a break-down of this 
immune surveillance system. CD8( + ) T cells will be obtained from an uninfected 
identical twin of an HIV-infected patient and transduced with the vector, 
Cr/az/4SVGF3e-, which contains a hybrid gene that activates the signal transduction 
system for T cell activation. This hybrid gene includes two components: (1) the 
extracellular domain of human CD4 (the receptor for the HIV envelope protein), and 
(2) the intracellular domain of the zeta (C) chain of the T cell receptor. The transduced 
T cells will be activated in the presence of HIV envelope proteins without major 
histocompatibility complex restriction. The genetically modified cells will be purified and 
expanded to large numbers in vitro prior to infusion into the HIV-infected twin. The 
study is divided into two phases. The first phase involves a single administration of 
transduced T cells to determine a maximum tolerated safe dose. The second phase 
involves ^ 6 infusions of this maximum tolerated dose. Subjects will be evaluated for the 
safety and tolerance of adoptive immunotherapy with the transduced CD8( -t- ) T cells, 
including monitoring of their immune status, viral burden, clinical symptoms, organ 
function, and persistence of circulating marked cells. This study will provide baseline 
information for future studies. 
Dr. Post explained that the investigators have adequately responded to the following 
questions raised in his primary written review: (1) Is there preclinical data that supports 
this protocol? The investigators subsequently provided a manuscript that describes the 
prechnical studies. (2) Is there additional information available about this new vector? 
The investigators responded that the vector, Cr^4SVGF3e-, was developed to allow 
high level expression of the transgene following transduction into human T cells. This 
vector is similar to the LXSN vector previously approved by the RAC; however, a 
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