Anti–PD-1 chimeric antigen receptor T cells efficiently target SIV-infected CD4+ T cells in germinal centers
Karsten Eichholz, … , Afam A. Okoye, Lawrence Corey
Karsten Eichholz, … , Afam A. Okoye, Lawrence Corey
Published April 1, 2024
Citation Information: J Clin Invest. 2024;134(7):e169309. https://doi.org/10.1172/JCI169309.
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Research Article AIDS/HIV

Anti–PD-1 chimeric antigen receptor T cells efficiently target SIV-infected CD4+ T cells in germinal centers

Abstract

Programmed cell death protein 1 (PD-1) is an immune checkpoint marker commonly expressed on memory T cells and enriched in latently HIV-infected CD4+ T cells. We engineered an anti–PD-1 chimeric antigen receptor (CAR) to assess the impact of PD-1 depletion on viral reservoirs and rebound dynamics in SIVmac239–infected rhesus macaques (RMs). Adoptive transfer of anti–PD-1 CAR T cells was done in 2 SIV-naive and 4 SIV-infected RMs on antiretroviral therapy (ART). In 3 of 6 RMs, anti–PD-1 CAR T cells expanded and persisted for up to 100 days concomitant with the depletion of PD-1+ memory T cells in blood and tissues, including lymph node CD4+ follicular helper T (TFH) cells. Loss of TFH cells was associated with depletion of detectable SIV RNA from the germinal center (GC). However, following CAR T infusion and ART interruption, there was a marked increase in SIV replication in extrafollicular portions of lymph nodes, a 2-log higher plasma viremia relative to controls, and accelerated disease progression associated with the depletion of CD8+ memory T cells. These data indicate anti–PD-1 CAR T cells depleted PD-1+ T cells, including GC TFH cells, and eradicated SIV from this immunological sanctuary.

Authors

Karsten Eichholz, Yoshinori Fukazawa, Christopher W. Peterson, Francoise Haeseleer, Manuel Medina, Shelby Hoffmeister, Derick M. Duell, Benjamin D. Varco-Merth, Sandra Dross, Haesun Park, Caralyn S. Labriola, Michael K. Axthelm, Robert D. Murnane, Jeremy V. Smedley, Lei Jin, Jiaxin Gong, Blake J. Rust, Deborah H. Fuller, Hans-Peter Kiem, Louis J. Picker, Afam A. Okoye, Lawrence Corey

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Figure 3

Anti–PD-1 CAR T cells expand in vivo and deplete PD-1+ CD4+ and CD8+ T cells in an SIV-naive RM.

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Anti–PD-1 CAR T cells expand in vivo and deplete PD-1+ CD4+ and CD8+ T c...
Schematic of the in vivo animal study in SIV-naive RMs (n = 2). Dates for tissue surgery, lymphodepletion, and tocilizumab treatment are noted (A). EGFRt and PD-1 cell marking in total CD3+ T cells in vivo at days 8 and 14 indicates robust expansion of anti-PD1 CAR T cells in RM1 (B). Longitudinal PBMC sampling in RM1 and RM2 for percentages of total CAR T cells in CD3+ T cells (C) and PD-1+ in CD4+ and CD8+ T cells (D). Nx, necropsy. Flow cytometric analysis of EGFR+ CD4+ or CD8+ CAR T cells in peripheral blood in RM1 (E). Expansion of CAR T cells in Peri.LN of RM1 (F). Depletion of PD-1–expressing TFH cells in LNs was assessed by flow cytometry (G). Combined multicolor IHC and RNA FISH for CD3 (green), CD20 (red), PD-1, CD8α RNA (blue), and CAR RNA (cyan) on B cell follicles of mes.LNs on days –10, 8, and 24 relative to infusion. White arrows indicate the location of anti–PD-1 CAR CD8+ T cells (H). Original magnification, ×40.