Presentation Abstract

Session: 087-HIV Pathogenesis Resistance and Diagnostics
Wednesday, Sep 11, 2013, 11:00 AM - 1:00 PM
Presentation Title: H-674 - Host Immune Environment Significantly Impact the Level of CD4 Reconstitution and the Effects on Latent Reservoir in HIV Subjects Receiving ZFN CCR5 Modified CD4 T-cells (SB-728-T)
Location: Exhibit Hall A
Presentation Number: H-674
Pres. Time: Wednesday, Sep 11, 2013, 11:00 AM - 1:00 PM
Category: H
Keywords: CCR5; cell therapy; CD4 reconstitution
Author(s): J. Zeidan1, G. Lee2, J. Lalezari3, R. Mitsuyasu4, S. Wang2, M. Giedlin2, W. Tang2, G. Nichol2, D. Ando2, R-P. Sekaly1;
1VGTI, Port St. Lucie, FL, 2Sangamo BioSci., Richmond, CA, 3Quest Clin. Res., San Francisco, CA, 4UCLA, Los Angeles, CA
Financial Disclosures:  J. Zeidan,
Sangamo BioSciences Role(s): Research Relationship.
G. Lee,
Sangamo BioSciences Role(s): Employee.
J. Lalezari,
Sangamo BioSciences Role(s): Investigator.
R. Mitsuyasu,
Sangamo BioSciences Role(s): Investigator.
S. Wang,
Sangamo BioSciences Role(s): Employee.
M. Giedlin,
Sangamo BioSciences Role(s): Employee.
W. Tang,
Sangamo BioSciences Role(s): Employee.
G. Nichol,
Sangamo BioSciences Role(s): Employee.
D. Ando,
Sangamo BioSciences Role(s): Employee.
R. Sekaly,
Sangamo BioSciences Role(s): Research Relationship.
Abstract: Background: Long term improvement in CD4 count was observed in all SB-728-T treated subjects, at levels greater than previous HIV/ T-cell studies. At 12 months post infusion, 5 of 9 subjects showed greater improved CD4 count (high CD4 responders; median increase= 224 cells/uL) than 4 other subjects (suboptimal responders; 44 cells/uL). Persistence of CCR5 modified cells mirrored this observation (34 v 24 CCR5 modifications/uL). Here, we performed phenotypic and transcriptional analyses to elucidate the role of inflammation on CD4 reconstitution and SB-728-T persistence, which may be critical in effecting the latent reservoir. Methods: 9 aviremic HIV+ subjects on ART with CD4 counts btw 200-500 cells/uL (known as “immune failures”) received 10-30E9 SB-728-T. Analyses of survival and activation markers were performed on PBMCs collected pre infusion, at early (D14-M2), mid (M4-7), and late (M9-12) time points post infusion. Results: Long term CD4 reconstitution is primarily driven by the central memory T-cell subset (TCM). Persistence of CCR5 modified cells does not fully explain the CD4 increases observed in high CD4 responders. High CD4 responders showed reduced PD-L1 expression in monocytes that correlates with lower PD-1 expression in TCM (r=.77, p=.02) and higher TCM counts (r=.83, p=.01) at M9. Importantly, the associated improvement in CD4 count at M12 correlates with decreased size of the latent reservoir (r=-.86, p=.02). Analysis of innate immune activation, as measured by expression of HLA-DR, CD80 and CD40 in monocytes, and IFN type I stimulated gene expression pre infusion showed that suboptimal responders had higher inflammation levels at baseline (r=-.73, p=.03). Conclusions: Reduction of PD-1/PD-L1 mediated suppression in TCM in high CD4 responders suggests that decreased levels of inflammation may provide a survival advantage of TCM post infusion. This may play a role in the observed decrease in latent reservoir size in subjects with superior long term improvement in CD4. Identification of an inflammatory signature prior to treatment as an important predictor of response will help future study design of SB-728-T.




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