CAR/CXCR5-T cell immunotherapy is safe and potentially efficacious in promoting sustained remission of SIV infection

Abstract

During chronic human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) infection prior to AIDS progression, the vast majority of viral replication is concentrated within B cell follicles of secondary lymphoid tissues. We investigated whether infusion of T cells expressing an SIV-specific chimeric antigen receptor (CAR) and the follicular homing receptor, CXCR5, could successfully kill viral-RNA+ cells in targeted lymphoid follicles in SIV-infected rhesus macaques. In this study, CD4 and CD8 T cells from rhesus macaques were genetically modified to express antiviral CAR and CXCR5 moieties (generating CAR/CXCR5-T cells) and autologously infused into a chronically infected animal. At 2 days post-treatment, the CAR/CXCR5-T cells were located primarily in spleen and lymph nodes both inside and outside of lymphoid follicles. Few CAR/CXCR5-T cells were detected in the ileum, rectum, and lung, and no cells were detected in the bone marrow, liver, or brain. Within follicles, CAR/CXCR5-T cells were found in direct contact with SIV-viral RNA+ cells. We next infused CAR/CXCR5-T cells into ART-suppressed SIV-infected rhesus macaques, in which the animals were released from ART at the time of infusion. These CAR/CXCR5-T cells replicated in vivo within both the extrafollicular and follicular regions of lymph nodes and accumulated within lymphoid follicles. CAR/CXR5-T cell concentrations in follicles peaked during the first week post-infusion but declined to undetectable levels after 2 to 4 weeks. Overall, CAR/CXCR5-T cell-treated animals maintained lower viral loads and follicular viral RNA levels than untreated control animals, and no outstanding adverse reactions were noted. These findings indicate that CAR/CXCR5-T cell treatment is safe and holds promise as a future treatment for the durable remission of HIV.

CD8+ T-cell responses in HIV controllers: potential implications for novel HIV remission strategies

“…Taken together, these data suggest that while HIV-specific CD8 + T cells in the lymph nodes from controllers may have a less effector differentiated phenotype compared to cells found in the blood, they nonetheless possess the capacity to expand and differentiate into potent antiviral effector cells and traffic to B cell follicles where the HIV reservoir persists. Several immune-based remission strategies are being developed to re-direct CD8 + T cells to the B cell follicles, including pharmacologic treatment with IL-15 agonists, genetically engineering CXCR5-expressing CD8 + T cells for adoptive transfer, and the development of bi-specific antibodies to redirect follicular CD8 + T cells to kill infected cells [103,104,105 ▪ ,106,107]. Implications:…”

Pre-clinical data supporting immunotherapy for HIV using CMV-HIV-specific CAR T cells with CMV vaccine

“…These findings hold promise of CAR T cell therapy for the durable remission of HIV. 49 Unlike other immunotherapies that require additional gene engineering to protect CD4 + CAR T cells from HIV infection, 16,50-52 most of our HIV pos donor-derived gene-modified T cells are CD8 + T cells and thus naturally resistant to HIV infection. The PBMCs used from HIVpositive donors are capable of supporting HIV infection but, within the combination of T cells, it is not known if the CAR T cells themselves become infected.…”

HIV-Specific CAR T Cells with CD28 or 4-1BB Signaling Domains Are Phenotypically and Functionally Distinct and Effective at Suppressing HIV and Simian Immunodeficiency Virus

“…Rhesus macaque PBMCs were transduced as described previously (26). Human PBMCs were transduced using identical methods, with the modification of using anti-human CD3 (clone OKT3 obtained from the National Cancer Institutes Biological Resources Branch Preclinical Repository) (7,26).…”

“…Importantly, addition of the MBL motif removes the entry-receptor function of the CD4 motif (6). Recently, we showed that infusion of T cells expressing an SIV-specific CD4-MBL-CAR and the CXCR5 follicular homing receptor (CAR/CXCR5 T cells) could successfully target viral RNA 1 cells in lymphoid follicles in SIV-infected rhesus macaques; however, the infused CAR/ CXCR5 T cells declined to undetectable levels after 24 wk (7). As these CAR/CXCR5 T cells were generated using a construct containing a CD28 costimulatory domain, we hypothesized that a different costimulatory domain might confer greater persistence of CAR/CXCR5 T cells.…”