[LbOr10] Development of genetically protected T-lymphocytes from transduced hematopoietic progenitors in human immunodeficiency virus-1 infected patients

14th International AIDS Conference

Barcelona, Spain — July 7-12, 2002

[TITLE:] Development of genetically protected T-lymphocytes from transduced hematopoietic progenitors in human immunodeficiency virus-1 infected patients

[AUTHOR(S):] Rafael Amado, Mitsuyasu RT, Ngok FK, Cole S, Chorn N, Lin LS, Bristol G, Miles SA¹, Rosenblatt JD², Bakker A³, Macpherson J, Fanning G, Todd A, Ely JA, Symonds GP⁴

Int Conf AIDS. 2002 Jul 7-12;14:Abstract No. LboR10

BACKGROUND: The cellular introduction of genetic elements that inhibits HIV is conceptually attractive as a new treatment paradigm for AIDS. By ex vivo retroviral transduction, we have introduced a HIV-1 (tat gene) targeted ribozyme (RRz2) and a control construct (LNL6) into G-CSF mobilized CD34+ hematopoietic progenitors.

METHODS: Transduced autologous CD34+ cells (RRz2+LNL6) were infused in equal numbers in ten patients in this Phase I study. At entry each patient had CD4+ counts between 300-700/mm³ and viral loads of <10,000 copies/ml. Median follow-up is 2.5 years. Gene presence was detected by a sensitive PCR assay. Relative amounts of vector were analyzed using mixed-effect linear regression.

RESULTS: We observed no toxicity related to gene transfer. The degree (0.1 to 0.01%) and persistence of gene marking in progeny cells was dependent on the cell dose infused (range 0.01-5.34x106/kg) with a minimum dose of 0.5x106/kg required for log-term gene persistence (>2.5 years). Expression of both constructs was detected in peripheral blood mononuclear cells obtained over one year after CD34+ infusion. Marking persisted in granulocytes, monocytes, lymph nodes, bone marrow, and in mature and naïve CD4+ and CD8+ cells, up to 3 years post-infusion. Gene presence in naïve thymocytes was observed in patients with viremia up to 22,628 copies/ml. Compared to control construct-containing T-cells, significantly longer survival was seen for RRz2-containing T-cells. No preferential survival was observed for RRz2-containing CD4- cells.

CONCLUSIONS: These findings demonstrate that de novo T-cell development can occur from genetically engineered hematopoietic progenitors in adult HIV-infected patients. This, together with the preferential survival of ribozyme-containing T-lymphocytes, supports the concept of gene therapy as a modality to effect immune reconstitution. A phase II trial to assess efficacy has been developed.

Presenting author: Rafael Amado

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1Department of Medicine, UCLA AIDS Institute, Department of Microbiology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.

2Department of Medicine, University of Miami, Miami, FL 33136, USA.

3Specialty Laboratories, Santa Monica, CA 90404, USA.

4Johnson & Johnson Research Pty Limited, Sydney 2012, Australia.

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