Suspected Immune-Related Adverse Events With an Anti-PD-1 Inhibitor in Otherwise Healthy People With HIV

Bosch, Ronald J.; McKahnn, Ashley; Moseley, Kendall F.; Wimbish, Chanelle; Hendrickx, Steven; Messer, Michael; Furlong, Maureen; Campbell, Danielle; Jennings, Cheryl; Benson, Constance A.; Overton, Edgar Turner; Macatangay, Bernard; Kuritzkes, Daniel R.; Miller, Elizabeth; Tressler, Randall; Eron, Joseph J.; Hardy, William; Team, Actg A Study

doi:10.1097/qai.0000000000002716

Cited by 17 publications

(18 citation statements)

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“…Humanised anti‐TIGIT mAbs are in early trials for use in cancer therapy, and anti‐PD‐1 treatment is being investigated in clinical studies targeting cancer and, to a limited extent, latent HIV‐1 reservoirs expressing PD‐1. 69 , 70 Treatment with anti‐PD‐1 was generally well‐tolerated in PLWH with controlled HIV‐1 viral loads, and future inclusion of PLWH in immunotherapy trials will inform whether anti‐TIGIT mAb is tolerated to the same extent as in HIV‐seronegative participants. 70 …”

Section: Discussionmentioning

confidence: 99%

TIGIT blockade enhances NK cell activity against autologous HIV‐1‐infected CD4⁺ T cells

2021

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Objectives. During chronic human immunodeficiency virus (HIV)-1 infection, inhibitory molecules upregulated on lymphocytes contribute to effector cell dysfunction and immune exhaustion. People living with HIV (PLWH) are at greater risk for age-related morbidities, an issue magnified by human cytomegalovirus (CMV) coinfection. As CMV infection modifies natural killer (NK) cell properties and NK cells contribute to protection against HIV-1 infection, we considered the role of T-cell immunoreceptor with immunoglobulin and intracellular tyrosine inhibitory motif domains (TIGIT) in NK cell-based HIV-1 immunotherapy and elimination strategies. Methods. We measured TIGIT expression on immune cell subsets of 95 PLWH and assessed its impact on NK cell function, including elimination of autologous CD4 + T cells infected through reactivation of endogenous HIV-1. Results. TIGIT was expressed on CD4 + T cells, CD8 + T cells and NK cells from PLWH. Although TIGIT levels on T cells correlated with HIV-1 disease progression, the extent of TIGIT expression on NK cells more closely paralleled adaptation to CMV. TIGIT interacts with its predominant ligand, poliovirus receptor (PVR), to inhibit effector cell functions. Circulating CD4 + T cells from PLWH more frequently expressed PVR than HIV-seronegative controls, and PVR expression was enriched in CD4 + T cells replicating HIV-1 ex vivo. Treatment with anti-TIGIT monoclonal antibodies increased NK cell HIV-1specific antibody-dependent cytotoxicity in vitro and ex vivo. Conclusion. Blocking TIGIT may be an effective strategy to invigorate antibody-dependent NK cell activity against HIV-1 activated in cellular reservoirs for cure or treatment strategies.

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Section: Discussionmentioning

confidence: 99%

TIGIT blockade enhances NK cell activity against autologous HIV‐1‐infected CD4⁺ T cells

2021

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“…More recently, a dose-escalation study of the anti-PD-1 antibody, cemiplimab, in PWH on ART without cancer, was stopped prematurely as possible immune-related adverse events (irAE) occurred in two of four cemiplimab recipients. 69 One participant developed thyroiditis assessed as probably related to cemiplimab while another had asymptomatic grade 3 hepatitis possibly related to cemiplimab. Both cases fully resolved without therapeutic intervention.…”

Section: Clinical Data Of Immune Checkpoint Blockers In Pwhmentioning

confidence: 99%

Immune checkpoint blockade in HIV

et al. 2022

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“…The CTLA-4 blocker reduced plasma viremia in proportion to drug concentration [ 88 ]. Safety is a significant challenge, as indicated by the immune-related adverse events (irAEs) that appeared in two clinical trials using a PD-1 blocker for HIV-infected individuals without malignancies [ 89 , 95 ]. Multiple injections of low doses of IC blocker might alleviate the side effects.…”

Section: Therapeutic Effects Of Immune Checkpoint Blockers On Hiv/siv...mentioning

confidence: 99%

Expression Profile and Biological Role of Immune Checkpoints in Disease Progression of HIV/SIV Infection

Sun

Xue

2022

Viruses

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During HIV/SIV infection, the upregulation of immune checkpoint (IC) markers, programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), T cell immunoglobulin and ITIM domain (TIGIT), lymphocyte-activation gene-3 (LAG-3), T cell immunoglobulin and mucin domain-3 (Tim-3), CD160, 2B4 (CD244), and V-domain Ig suppressor of T cell activation (VISTA), can lead to chronic T cell exhaustion. These ICs play predominant roles in regulating the progression of HIV/SIV infection by mediating T cell responses as well as enriching latent viral reservoirs. It has been demonstrated that enhanced expression of ICs on CD4+ and CD8+ T cells could inhibit cell proliferation and cytokine production. Overexpression of ICs on CD4+ T cells could also format and prolong HIV/SIV persistence. IC blockers have shown promising clinical results in HIV therapy, implying that targeting ICs may optimize antiretroviral therapy in the context of HIV suppression. Here, we systematically review the expression profile, biological regulation, and therapeutic efficacy of targeted immune checkpoints in HIV/SIV infection.

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Suspected Immune-Related Adverse Events With an Anti-PD-1 Inhibitor in Otherwise Healthy People With HIV

Cited by 17 publications

References 10 publications

TIGIT blockade enhances NK cell activity against autologous HIV‐1‐infected CD4⁺ T cells

TIGIT blockade enhances NK cell activity against autologous HIV‐1‐infected CD4⁺ T cells

Immune checkpoint blockade in HIV

Expression Profile and Biological Role of Immune Checkpoints in Disease Progression of HIV/SIV Infection

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Suspected Immune-Related Adverse Events With an Anti-PD-1 Inhibitor in Otherwise Healthy People With HIV

Cited by 17 publications

References 10 publications

TIGIT blockade enhances NK cell activity against autologous HIV‐1‐infected CD4+ T cells

TIGIT blockade enhances NK cell activity against autologous HIV‐1‐infected CD4+ T cells

Immune checkpoint blockade in HIV

Expression Profile and Biological Role of Immune Checkpoints in Disease Progression of HIV/SIV Infection

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Product

Resources

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TIGIT blockade enhances NK cell activity against autologous HIV‐1‐infected CD4⁺ T cells

TIGIT blockade enhances NK cell activity against autologous HIV‐1‐infected CD4⁺ T cells