Scientific Abstract 
Protocol Title: A Phase I/II Pilot Study of the Safety of the Adoptive Transfer of Syngeneic Gene- 
Modified Cytotoxic T Lymphocytes in HIV-Infected Identical Twins 
Scientific Abstract: The cell-mediated immune response plays an essential role in the host's defense 
against viral infection. Studies of cytomegalovirus (CMV) and influenza virus for which small animal 
models are available have revealed that CD8+ cytotoxic T lymphocytes (CTLs) represent the major 
component of this cellular immunity. Although optimal animal models for HTV infection await 
development, evidence that CD8-f- CTLs represent the major and earliest immune response to HIV 
infection is supported by correlative data from HIV-infected patients. The clinical data available 
suggest that a breakdown of the host cell-mediated immune response may be responsible for 
progression to symptomatic AIDS. In vitro studies have not only confirmed that HlV-specific CD8-I- 
T cells exhibit cytolytic activity toward HIV-infected targets, but have also revealed that CD8+ T cells 
have the ability to inhibit replication of HIV in lymphocyte cultures. Data supportive of the central role 
of CD8-I- T cells in HIV infection suggest that adoptive transfer of HlV-specific CD8+ T cells may 
have potential as an immunotherapy for HIV-infected individuals. 
Cell Genesys, Inc. has designed universal (HLA-unrestricted) chimeric T cell receptors (URs) that can 
redirect the antigenic specificity of peripheral blood mononuclear cell (PBMC)-derived CD8-f T cell 
populations to recognize HIV antigen(s) of choice expressed on the surface of infected cells. Upon 
binding to viral antigen, these URs initiate T cell activation, resulting in induction of effector functions 
including cytolysis of the virally-infected cell. The URs developed to date are chimeric receptors 
composed of antigen recognition and signaling domains. The UR proposed for initial clinic^ 
investigation is composed of the extracellular domain of the human CD4 receptor that recognizes the 
gpl20 moiety of HIV env fused to the cytoplasmic domain of zeta, responsible for signal transduction 
in T cells. Using retroviral-mediated transduction with replication-defective retroviral vectors, we can 
routinely generate CD8+ T cells stably expressing high levels of HlV-specific URs. The UR+ CD8+ 
T cell population exhibits highly efficient cytolytic activity against T cells infected with HIV-1. In 
addition, preliminary findings show inhibition of viral replication of a low passage lymphocytotropic 
strain of HIV-1. 
In a collaborative clinical study between Cell Genesys, Inc. and investigators at the NIH, we will 
assess the safety and tolerance of adoptive transfer of anti-HIV cytotoxic, syngeneic peripheral blood T 
lymphocytes containing the CD4-UR into patients with HIV infection. The donors for the CD8-t- T 
cells will be HLA-identical seronegative twins of the HIV-positive patients. The proposed study is an 
open-label, comparative, sequentially randomized treatment with genetically unmodified or modified ex 
v/vo-expanded T lymphocytes. The study is divided into two treatment periods. In the initial period, 
single doses of genetically unmodified T lymphocytes or single, escalating doses of genetically 
modifed T lymphocytes will be administered. In the second period, multiple doses of the maximum 
tolerated cell dose will be administered. By monitoring functional immune status, viral burden, clinical 
symptoms, organ function, and persistence of circulating gene-modified T lymphocytes, we hope to 
determine whether this potential therapeutic approach is feasible and safe. This study may form the 
baseline for future protocols using lymphocytes obtained directly from HIV patients. 
Recombinant DNA Research, Volume 19 
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