- Category: Search for a Cure
- Published on Thursday, 20 September 2012 00:00
- Written by Liz Highleyman
Gene therapy using a zinc finger nuclease that makes CD4 T-cells resistant to HIV infection led to long-term gains in CD4 cell counts among HIV positive people with poor immunological recovery on antiretroviral therapy (ART), researchers reported at the 52nd Interscience Conference on Antimicrobials and Chemotherapy (ICAAC) last week in San Francisco. Transitional memory T-cells appeared to account for most of the increase.
Despite the availability of effective antiretroviral treatment, a cure remains the ultimate goal of HIV research. One approach involves genetic manipulation of T-cells -- or their hematopoietic stem cell precursors -- to delete the CCR5 surface co-receptor, which most types of HIV use to center cells.
Sangamo Biosciences has developed a technique in which T-cells are collected from a patient's blood via apheresis, a zinc finger nuclease is used to disrupt CCR5 gene expression, and the altered cells -- known as SB-728-T cells-- are allowed to multiply and infused back into the body.
Researchers in San Francisco and Philadelphia have previously reported that the procedure appears safe and well-tolerated, the modified CD4 cells engraft and distribute themselves as expected in the body, and treated patients show sustained T-cell gains and improvement of CD4:CD8 cell ratios.
At ICAAC, Joumana Zeidan from the Vaccine and Gene Therapy Institute in Port St Lucie, Florida, presented findings from a small study of cell expansion in a subset of people who received the zinc finger nuclease treatment in clinical trials. The researchers wanted to know if preferential expansion of specific types of CD4 T-cells -- for example, naive cells, central memory cells, transitional memory cells, or effector memory cells -- accounted for observed gains.
This analysis included 9 HIV positive people who maintained undetectable HIV viral load on ART but whose CD4 count remained in the 200-500 cells/mm3 range. Participants received single infusions containing 5 billion to 30 billion modified SB-728-T cells.
- Participants experienced significant CD4 cell increases from baseline, with median gains of 223 cells/mm3 at 14 days, 164 cells/mm3 at 6 months, and 93 cells/mm3 at 12 months; however, gains varied widely among individuals.
- 5 of 9 patients achieved CD4 levels above 500 cells/mm3, until recently considered the threshold for ART initiation (the latest U.S. guidelines recommend starting treatment regardless of CD4 count).
- Naive cells, including recent thymic emigrants, did not contribute significantly to the observed CD4 cell increases.
- Gains were primarily due to increases in transitional memory T-cells, but participants also saw increases in central memory T-cells.
- Transitional and effector memory SB-728-T cells showed high levels of expression of activation markers such as HLA-DR, CD28, and CD25.
- No major safety issues were identified.
The lack of increase in recent thymic emigrant naive T-cells "suggests that production of new T-cells by the thymus is not implicated in the sustained increase of CD4 T-cells," the researchers explained.
Rather, the frequency of transitional memory cells expressing activation markers "suggests that the activated transitional memory SB-728-T product cells expand following infusion and account for the early changes in CD4 counts."
"Subjects with more robust increases in CD4 counts had greater central memory CD4 T-cell reconstitution," they continued. "Durable increase in CD4 T-cells may be due to enhanced survival and differentiation of the endogenous central memory CD4 T-cells."
"These preliminary data suggest that SB-728-T has the attributes to provide sustained improvement in the CD4 compartment and the potential to reconstitute the immune system," they concluded.
J Zeidan, R Bordi, S Deeks, et al. Preferential Expansion of Transitional (TTM) and Central Memory (TCM) CD4 T-cells following Adoptive Transfer of ZFN CCR5 Modified Autologous CD4 T-cells (SB-728-T). 52nd Interscience Conference on Antimicrobials and Chemotherapy. San Francisco. September 9-12, 2012. Abstract H-553.