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Abstract
Immune therapy of advanced HIV-1 infection by transduced autologous T helper cells expressing a peptide which inhibits viral entry. Results of a phase I pilot study.
van Lunzen J.1, Glaunsinger T.1, Stahmer I.1, Kühlcke K.2, Schilz A.2, Stellbrink H.J.1, Mayr C.3, Dinauer N.4, Alexandrov A.4, von Laer D.5
1University Medical Center Eppendorf, Hamburg, Germany, 2EUFETS AG, Idar-Oberstein, Germany, 3Private Practice Seestrasse, Berlin, Germany, 4Fresenius Biotech AG, Bad Homburg, Germany, 5Georg-Speyer-Haus, Frankfurt, Germany
Introduction: Despite significant improvements of HAART, limitations such as drug resistance and toxicities call for innovative strategies.
Objective: To develop an effective HIV gene therapy involving the ex vivo transfer of an antiviral gene into autologous CD4+ T cells.
Methods: A novel antiviral gene (M87o) was cloned into a retroviral vector backbone inhibiting virus entry by expressing a membrane anchored peptide derived from the second heptad repeat of gp41. Autologous T cells obtained by lymphapheresis were expanded ex vivo and transfected. Gene modified CD4+ T cells were transfused into pts. with advanced disease (CD4 <200/µl) and failing HAART (VL >5000 c/ml) due to MDR viruses and followed in vivo by qPCR in LN and PB.
Results: M87o inhibited virus entry for all HIV isolates tested with 99-100% efficiency. A median of 1.26 x 109 transfected T cells were retransfused into 10 pts. with advanced disease (median CD4 93/µl, VL 4.96 log10 c/ml). No severe side effects or grade 3-4 AE`s occurred. Transduced T cells enriched in the PB immediately after retransfusion leading to a gene marking of 20% of peripheral CD4+ T cells. Rapid redistribution to LN was observed where transduced T cells could be detected up to 9 mths. In 6/10 pts. a significant increase (>50%) of CD4 counts was observed despite unchanged HAART. Mean relative increase at week 12 was 43% compared to baseline (110/µl to 153/µl) with no significant changes of VL. A positive correlation between the absolute number of transfected CD4 T cells and increases of CD4 counts was observed.
Conclusions: This first gene therapeutic approach for HIV infection based on entry inhibition shows promising results. Transduced CD4+ T cells have been transfused safely leading to an increase of circulating CD4+ T cells. This increase in app. 60% of these advanced patients warrant further trials in less immunocompromised cohorts.
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