Journal Article

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

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

2024

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Acquired immune deficiency syndrome / Adoptive transfer / AIDS / AIDS/HIV / Animals / Antibodies / Antigens / Antiretroviral drugs / Antiretroviral therapy / Apoptosis / CD4 antigen / CD4-Positive T-Lymphocytes - immunology / CD8 antigen / Cell death / Chimeric antigen receptors / Disease / Drug therapy / Germinal Center - immunology / Germinal centers / HIV / HIV Infections - therapy / Human immunodeficiency virus / Immune checkpoint / Immunological memory / Infections / Lymph nodes / Lymphatic system / Lymphocytes / Lymphocytes T / Lymphoma / Macaca mulatta - metabolism / Memory cells / PD-1 protein / Programmed Cell Death 1 Receptor / Proteins / Receptors, Chimeric Antigen - genetics / Simian Acquired Immunodeficiency Syndrome - therapy / Simian Immunodeficiency Virus / Therapeutics / Viremia