Adoptive Transfer of Haploidentical NK Cells and N-803
Condition: Hiv; HIV Infections; Immune Deficiency
MeSH terms: Immunologic Deficiency Syndromes
Study type: Interventional
Phase: Phase 1

Summary: 
      This is a pilot therapeutic study of related donor HLA-haploidentical NK-cell based therapy
      to determine if the treatment is safe and well-tolerated and if there is any measureable
      impact on virus reservoirs.
    

Detailed description: 
      Human immunodeficiency virus (HIV) infection causes profound and often irreversible changes
      to the adaptive and innate immune system. In the absence of antiretroviral therapy (ART),
      Cluster of Differentiation (CD)4+ T cells are progressively depleted, CD8+ T cells are often
      expanded, and much of the immune system is chronically activated. Much of these abnormalities
      improve during long-term ART, but the system rarely returns to normal. Notably, chronic
      inflammation persists indefinitely during ART, and is driven by multiple factors, including
      HIV production (and perhaps replication), irreversible loss of the mucosal integrity and
      exposure to gut microbes, and an excess burden of other pathogens such as cytomegalovirus
      (CMV). How the virus and its host interact during effective ART is the focus of intense
      investigation.

      HIV-1 preferentially infects activated memory CD4+ T cells that express the chemokine
      receptor CCR5, although resting CD4+ T cells, naïve CD4+ T cells and macrophages can also be
      infected. The majority of infected and activated CD4+ T cells die quickly, but a small
      fraction reverts to a resting state and persistent indefinitely as the latent reservoir.
      Because ART blocks all or nearly all new infection events, the reservoir that exists at the
      time ART is initiated becomes the reservoir that persists for the life of the individual.
      This memory T cell viral reservoir is maintained during ART by the long half-life of the
      infected cell, homeostatic proliferation of these cells and perhaps by low levels of
      persistent viral replication.

      The viral reservoir in peripheral blood exists predominantly in those longer-lived memory
      CD4+ cells endowed with regenerative potential, including memory stem cells, central memory
      cells and transitional memory. The reservoir also persists in potentially shorter-lived CD4+
      T effector cell populations, but whether these cells represent a stable reservoir or one that
      is constantly being regenerated via proliferation and differentiation is unknown.

      "Shock and Kill". One approach to curing HIV infection that has generated broad support in
      the field is to induce latently infected cells to produce virus (the "shock") while enhancing
      the ability of the host to clear these virus-producing cells (the "kill"). Histone
      deacetylase (HDAC) inhibitors have been shown to increase production of HIV-1 RNA and to a
      lesser degree virus particles from the viral reservoir in vivo. The magnitude of the effect
      of HDAC inhibitors is modest at best, and as of yet this class of drugs has had no consistent
      effect on the frequency of cells that harbor replication-competent HIV. Other classes of
      anti-latency drugs and immunomodulators are therefore being explored for their capacity to
      stimulate the viral reservoir.

      To augment the capacity of the host to eliminate reservoir cells following activation,
      several immunologic strategies are being explored. These strategies include therapeutic
      vaccines, monoclonal antibodies, and immune checkpoint inhibitors.
    

Intervention name(s): Haploidentical Natural Killer (NK) Cells
Intervention type(s): Biological
Intervention description(s): infusion with N-803 activated NK cells
Intervention model: Single Group Assignment
Intervention model description: Non-controlled intervention groups
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Suppressive Antiretroviral Therapy (ART)