Abstract
The introduction and expression of genes in somatic cells is an innovative therapy for correcting genetic deficiency diseases and augmenting immune function. A potential obstacle to gene therapy is the elimination of such gene–modified cells by an immune response to novel protein products of the introduced genes. We are conducting an immunotherapy trial in which individuals seropositive for human immunodeficiency virus (HIV) receive CD8+ HIV–specific cytotoxic T cells modified by retroviral transduction to express a gene permitting positive and negative selection. However, five of six subjects developed cytotoxic T–lymphocyte responses specific for the novel protein and eliminated the transduced cytotoxic T cells. The rejection of genetically modified cells by these immunocompromised hosts suggests that strategies to render gene–modified cells less susceptible to host immune surveillance will be required for successful gene therapy of immunocompetent hosts.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Miller, A.D. Human gene therapy comes of age. Nature 357, 455–460 (1992).
Anderson, W.F. Human gene therapy. Science 256, 808–813 (1992).
Yang, Y. et al. Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc. Natl. Acad. Sci. USA 91, 4407–4411 (1994).
Yang, Y. et al. Inactivation of E2a in recombinant adenoviruses improves the prospect for gene therapy in cystic fibrosis. Nature Genet. 7, 362–369 (1994).
Simon, R.H. et al. Adenovirus-mediated transfer of the CFTR gene to lung of nonhuman primates: Toxicity study. Hum. Gene Ther. 4, 771–780 (1993).
Yei, S.P., Mittereder, N., Tang, K., O'Sullivan, C. & Trapnell, B.C. Adenovirus-mediated gene transfer for cystic fibrosis — quantitative evaluation of repeated in vivo vector administration to the lung. Gene Ther. 1, 192–200 (1994).
Yang, Y., Li, Q., Ertl, H.C. & Wilson, J.M. Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses. J. Virol. 69, 2004–2015 (1995).
Dai, Y. et al. Cellular and humoral immune responses to adenoviral vectors containing factor IX gene: Tolerization of factor IX and vector antigens allows for long-term expression. Proc. Natl. Acad. Sci. USA 92, 1401–1405 (1995).
Zsengeller, Z.K. et al. Persistence of replication-deficient adenovirus-mediated gene transfer in lungs of immune-deficient (nu/nu) mice. Hum. Gene Ther. 6, 457–467 (1995).
Brody, S.L., Metzger, M., Danel, C., Rosenfeld, M.A. & Crystal, R.G. Acute responses of nonhuman primates to airway delivery of an adenovirus vector containing the human cystic fibrosis transmembrane conductance regulator cDNA. Hum. Gene Ther. 5, 821–836 (1994).
Crystal, R.G. et al. Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nature Genet. 8, 42–51 (1994).
Ulmer, J.B. et al. Heterologous protection against influenza by injection of DNA encoding a viral protein. Science 259, 1745–1749 (1993).
Michel, M.L. et al. DNA-mediated immunization to the hepatitis B surface antigen in mice: Aspects of the humoral response mimic hepatitis B viral infection in humans. Proc. Natl. Acad. Sci. USA 92, 5307–5311 (1995).
Raz, E. et al. Intradermal gene immunization: The possible role of DNA uptake in the induction of Cellular immunity to viruses. Proc. Natl. Acad. Sci. USA 91, 9519–9523 (1994).
Dai, Y., Roman, M., Naviaux, R.K. & Verma, I.M. Gene therapy via primary myoblasts: Long-term expression of factor IX protein following transplantation in vivo. Proc. Natl. Acad. Sci. USA 89, 10892–10895 (1992).
Palmer, T.D., Rosman, G.J., Osborne, W.R. & Miller, A.D. Genetically modified skin fibroblasts persist long after transplantation but gradually inactivate introduced genes. Proc. Natl. Acad. Sci. USA 88, 1330–1334 (1991).
Culver, K.W. et al. In vivo expression and survival of gene-modified T lymphocytes in rhesus monkeys. Hum. Gene Ther. 1, 399–410 (1990).
van Beusechem, V.W., Kukler, A., Heidt, P.J. & Valerio, D. Long-term expression of human adenosine deaminase in rhesus monkeys transplanted with retrovirus-infected bone-marrow Cells. Proc. Natl. Acad. Sci. USA 89, 7640–7644 (1992).
Rosenberg, S.A. et al. Gene transfer into humans — immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N. Engl. J. Med. 323, 570–578 (1990).
Merrouche, Y. et al. Clinical application of retroviral gene transfer in oncology: Results of a French study with tumor-infiltrating lymphocytes transduced with the gene of resistance to neomycin. J. Clin. Oncol. 13, 410–418 (1995).
Blaese, R.M. et al. Treatment of severe combined immunodeficiency disease (SCID) due to adenosine deaminase deficiency with CD34+ selected autologous peripheral blood cells transduced with a human ADA gene. Amendment to clinical research project, Project 90-C-195, January 10, 1992. Hum. Gene Ther. 4, 521–527 (1993).
Rooney, C.M. et al. Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation. Lancet 345, 9–13 (1995).
Brenner, M.K. et al. Gene-marking to trace origin of relapse after autologous bone-marrow transplantation. Lancet 341, 85–86 (1993).
Brenner, M.K. et al. Gene marking to determine whether autologous marrow infusion restores long-term haemopoiesis in cancer patients. Lancet 342, 1134–1137 (1993).
Deisseroth, A.B. et al. Genetic marking shows that Ph+ cells present in autologous transplants of chronic myelogenous leukemia (CML) contribute to relapse after autologous bone marrow in CML. Blood 83, 3068–3076 (1994).
Kohn, D.B. et al. Engraftment of gene-modified umbilical cord blood Cells in neonates with adenosine deaminase deficiency. Nature Med. 1, 1017–1023 (1995).
Riddell, S.R. & Greenberg, P.D. Principles for adoptive T Cell therapy of human viral diseases. Annu. Rev. Immunol. 13, 545–586 (1995).
Riddell, S.R. et al. Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T Cell clones. Science 257, 238–241 (1992).
Walter, E.A. et al. Reconstitution of Cellular immunity against CMV in recipients of allogeneic bone marrow by adoptive transfer of T Cell clones from the donor. N. Engl. J. Med. 333, 1038–1044 (1995).
Koup, R.A. et al. Temporal association of Cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J. Viral. 68, 4650–4655 (1994).
Klein, M.R. et al. Kinetics of gag-specific cytotoxic T lymphocyte responses during the clinical course of HIV-1 infection: A longitudinal analysis of rapid progressors and long-term asymptomatics. J. Exp. Med. 181, 1365–1372 (1995).
Carmichael, A., Jin, X., Sissons, P. & Borysiewicz, L. Quantitative analysis of the human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T lymphocyte (CTL) response at different stages of HIV-1 infection: Differential CTL responses to HIV-1 and Epstein-Barr virus in late disease. J. Exp. Med. 177, 249–256 (1993).
Borrow, P., Lewicki, H., Hahn, B.H., Shaw, G.M. & Oldstone, M.B. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J. Virol. 68, 6103–6110 (1994).
Koenig, S. et al. Transfer of HIV-1-specific cytotoxic T lymphocytes to an AIDS patient leads to selection of mutant HIV variants and subsequent disease progression. Nature Med. 1, 330–336 (1995).
Baenziger, J., Hengartner, H., Zinkernagel, R.M. & Cole, G.A. Induction or prevention of immunopathological disease by cloned cytotoxic T cell lines specific for lymphocytic choriomeningitis virus. Eur. J. Immunol. 16, 387–393 (1986).
Matloubian, M., Concepcion, R.J. & Ahmed, R. CD4+ T Cells are required to sustain CD8+ cytotoxic T-Cell responses during chronic viral infection. J. Virol. 68, 8056–8063 (1994).
Lupton, S.D., Brunton, L.L., Kalberg, V.A. & Overell, R.W. Dominant positive and negative selection using a hygromycin phosphotransferase-thymidine kinase fusion gene. Mol. Cell Biol. 11, 3374–3378 (1991).
Borrelli, E., Heyman, R., Hsi, M. & Evans, R.M. Targeting of an inducible toxic phenotype in animal Cells. Proc. Natl. Acad. Sci. USA 85, 7572–7576 (1988).
Harty, J.T. & Bevan, M.J. CD8+ T Cells specific for a single nonamer epitope of Listeria monocytogenes are protective in vivo. J. Exp. Med. 175, 1531–1538 (1992).
Tigges, M.A. et al. Human CD8+ herpes simplex virus-specific cytotoxic T-lymphocyte clones recognize diverse virion protein antigens. J. Virol. 66, 1622–1634 (1992).
von Boehmer, H. & Kisielow, P. Self-nonself discrimination by T Cells. Science 248, 1369–1373 (1990).
Dranoff, G. & Mulligan, R.C. Gene transfer as cancer therapy. Adv. Immunol. 58, 417–454 (1995).
Chen, L. et al. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell 71, 1093–1102 (1992).
Townsend, S.E. & Allison, J.P. Tumor rejection after direct costimulation of CD8+ T Cells by B7-transfected melanoma Cells. Science 259, 368–370 (1993).
Yang, Y.P., Trinchieri, G. & Wilson, J.M. Recombinant IL-12 prevents formation of blocking IgA antibodies to recombinant adenovirus and allows repeated gene therapy to mouse lung. Nature Med. 1, 890–893 (1995).
York, I.A. et al. A cytosolic herpes simplex virus protein inhibits antigen presentation to CD8+ T lymphocytes. Cell 77, 525–535 (1994).
Fruh, K. et al. A viral inhibitor of peptide transporters for antigen presentation. Nature 375, 415–418 (1995).
Hill, A. et al. Herpes simplex virus turns off the TAP to evade host immunity. Nature 375, 411–415 (1995).
Riddell, S.R. & Greenberg, P.D. The use of anti-CD3 and anti-CD28 monoclonal antibodies to clone and expand human antigen-specific T Cells. J. Immunol. Methods 128, 189–201 (1990).
Riddell, S.R. et al. Phase 1 study of Cellular adoptive immunotherapy using genetically modified CD8+ HIV-specific T Cells for HIV seropositive patients undergoing allogeneic bone marrow transplant. Hum. Gene Ther. 3, 319–338 (1992).
Strijbosch, L.W., Buurman, W.A., Does, R.J., Zinken, P.H. & Groenewegen, G. Limiting dilution assays. Experimental design and statistical analysis. J. Immunol. Methods 97, 133–140 (1987).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Riddell, S., Elliott, M., Lewinsohn, D. et al. T–cell mediated rejection of gene–modified HIV–specific cytotoxic T lymphocytes in HIV–infected patients. Nat Med 2, 216–223 (1996). https://doi.org/10.1038/nm0296-216
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nm0296-216
This article is cited by
-
Tuning CARs: recent advances in modulating chimeric antigen receptor (CAR) T cell activity for improved safety, efficacy, and flexibility
Journal of Translational Medicine (2023)
-
Molecular imaging of cellular immunotherapies in experimental and therapeutic settings
Cancer Immunology, Immunotherapy (2022)
-
A rational blueprint for the design of chemically-controlled protein switches
Nature Communications (2021)
-
Immunogenicity of CAR T cells in cancer therapy
Nature Reviews Clinical Oncology (2021)
-
A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy
Nature Biotechnology (2020)