Important note: Information in this article was accurate in 1994. The state of the art may have changed since the publication date.
Reconstitution of viral immunity by the adoptive transfer of T-cell clones modified by gene insertion (Meeting abstract).
EACR-12: 12th Biennial Meeting of the European Association for Cancer Research. April 4-7, 1993, Brussels, Belgium, 1993.. Unique Identifier : AIDSLINE ICDB/94697579 Greenberg P; Watanabe K; Gilbert M; Nelson B; Riddell S; Univ. of Washington, Seattle, WA 98195
Abstract:
The essential role of CD8+ Tc for protection from CMV disease is supported by studies in which we demonstrated that patients who endogenously reconstitute their CMV-specific CD8+ Tc response are protected from the development of CMV disease, whereas patients lacking this response are at high risk for disease. Our initial adoptive T-cell therapy protocol is described. None of the patients who received adoptive T-cell therapy developed subsequent evidence of CMV disease. Our laboratory is now evaluating methods to improve the efficacy and safety of adoptive T-cell transfer by the introduction of genes into T-cell clones. To improve safety, a retroviral vector containing an inducible suicide gene has been constructed (Targeted Genetics Corporation): herpes virus thymidine kinase (TK) gene has been fused in frame with the hph gene, resulting in a gene encoding a single bifunctional protein (HyTK) conferring hygromycin resistance and in vitro sensitivity to ganciclovir. Studies in mice have demonstrated that T-cell clones expressing this gene can be readily eliminated in vivo by the administration of nontoxic doses of ganciclovir. A clinical trial employing T cells modified with this gene, now underway in HIV-seropositive patients undergoing allogeneic BMT for the treatment of HIV-related lymphomas is described. The therapeutic efficacy of transferred CD8+ T-cell clones in murine models is limited by the inability of the clones to proliferate and survive long-term in vivo in the absence of either exogenous IL-2 or a concurrent CD4+ helper T-cell response. Therefore, we are attempting to modify CD8+ T cells to render them independent of exogenous growth factors and capable of proliferating in response to TCR ligation. Several types of gene constructs are being evaluated. The first is designed to provide the additional signals necessary to result in endogenous IL-2 production following T-cell activation. Based on previous studies of bifunctional CD8+ T cells isolated from mice, CD8+ Tc clones were transduced with a vector containing the gene for the IL-1 receptor. Such T cells proliferate in response to binding of ligands to both the TCR and IL-1R, but fail to proliferate in response to either signal alone. A second type of construct involves the generation of a hybrid gene, in which the IL-2 coding sequence is under control of a promoter normally activated by TCR ligation. Preliminary studies are being performed with a vector containing the IFN-gamma promoter driving an IL-2 cDNA. Finally, a third type of construct containing chimeric cytokine receptors potentially capable of providing an autocrine loop and delivering to a T cell the signal normally provided by the binding of IL-2 to its receptor is being evaluated. Our initial studies are with a vector containing the extracellular domain of the c-kit receptor fused in frame to the transmembrane and intracytoplasmic domains of the IL-2 receptor beta and gamma chains. Binding of c-kit results in dimerization of the beta and gamma chains and delivery of the IL-2 receptor growth signal to T cells. Constructs fusing the extracellular binding domains of GM-CSF with the intracellular IL-2 receptor beta and gamma chains are now being prepared.
Keywords: Animal Antigens, CD8/CHEMISTRY Cell Division Cloning, Molecular Cytomegalovirus Infections/IMMUNOLOGY/*THERAPY DNA, Complementary/GENETICS Ganciclovir/THERAPEUTIC USE Human HIV Infections/DRUG THERAPY *Immunotherapy, Adoptive Interferon Type II/GENETICS Interleukin-2/GENETICS Mice Receptors, Antigen, T-Cell/METABOLISM Receptors, Interleukin-1/METABOLISM Simplexvirus/GENETICS T-Lymphocytes/PATHOLOGY T-Lymphocytes, Cytotoxic/IMMUNOLOGY Thymidine Kinase/GENETICS Zidovudine/THERAPEUTIC USE ABSTRACT 941230
M94C4336
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Important note: Information in this article was accurate in 1994. The state of the art may have changed since the publication date.
