The human IL-15 superagonist ALT-803 directs SIV-specific CD8+ T cells into B-cell follicles

Webb, Gabriela M.; Li, Shengbin; Mwakalundwa, Gwantwa; Folkvord, Joy M.; Greene, Justin M.; Reed, Jason S.; Stanton, Jeffrey J.; Legasse, Alfred W.; Hobbs, Theodore R.; Martin, Lauren Drew; Park, Byung; Whitney, James B.; Jeng, Emily K.; Wong, Hing C.; Nixon, Douglas F.; Jones, R. Brad; Connick, Elizabeth; Skinner, Pamela J.; Sacha, Jonah B.

doi:10.1182/bloodadvances.2017012971

Cited by 77 publications

(125 citation statements)

References 19 publications

(28 reference statements)

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“…Notably, the effects of IL-15 priming on NK cell metabolism and functionality have important implications for clinical translation in HIV-1 infection. The beneficial effects of IL-15 immunotherapy and IL-15 superagonist ALT-803, capable of activating both NK cells and CD8 T cells, have been highlighted in vivo in non-human primate models (Webb et al, 2018) and such an approach is currently being tested in a phase I clinical trial to facilitate clearance of latent HIV-1 reservoirs (NCT02191098). The ability of IL-15 to enhance ADCC and augment NK cell mediated killing of HIV-infected target cells ex vivo (Garrido et al, 2018) may prove vital in the development of a functional cure for HIV.…”

Section: Discussionmentioning

confidence: 99%

IL-15 re-programming compensates for NK cell mitochondrial dysfunction in HIV-1 infection

Cubero

Balint

Alrubayyi³

et al. 2019

Preprint

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16Dynamic regulation of cellular metabolism is important for maintaining homeostasis and can directly 17 influence immune cell function and differentiation including Natural Killer (NK) cell responses. 18Persistent HIV-1 infection leads to a state of chronic activation, subset redistribution and progressive 45 et al., 2015) (Lee et al., 2015). The adaptive reconfiguration of NK cells during HIV-1 infection is further 46 delineated by loss of the transcription factor promyelocytic leukaemia zinc finger protein (PLZF), and 47 downstream signalling molecules such as FcεRI-γ (Peppa et al., 2018), which partly overlap with 48 NKG2C expression. While these attributes are considered important in the functional specialisation of 49 2 these NK cells, the development of these features under conditions of continuous 50 stimulation/persistent inflammation during HIV-1 infection could lead to the establishment of 51 functionally and metabolically exhausted NK cells akin to exhausted CD8 T cells. In keeping with this 52 notion, chronic stimulation of adaptive NK cells through NKG2C ligation was recently found to lead to 53 a molecular programme of exhaustion that is shared between NK cells and CD8 T cells (Merino et al., 54 2019). Exhausted CD8 T cells are characterised by a number of metabolic defects, however, to date it 55 remains unexplored how persistent HIV-1 infection contributes to the metabolic remodelling of NK 56 cell subsets. NK cell exhaustion could influence responses to CD16 engagement linked to vaccine-57 induced protective immunity against HIV-1 infection and phenotypes of viral control (Scully and Alter, 58 2016). Such knowledge represents a critical first step in our understanding of the metabolic machinery 59 of NK cell subsets with distinct immunologic features that can be potentially targeted for developing 60 new or complementary antiviral approaches aimed at enhancing ADCC responses. 61 62 Whereas metabolic regulation of T cell function is well characterised, evidence of the importance of 63 immunometabolism in facilitating robust NK cell functions is gradually emerging. Notably, impaired 64 NK cell cellular metabolism has been implicated in obesity and cancer, providing a new framework for 65 understanding NK cell functionality (Michelet et al., 2018) (Cong et al., 2018). Studies from both 66 human and murine models have demonstrated that NK cells activated through cytokine stimulation 67 exhibit substantial increases in the rates of both glycolysis and oxidative phosphorylation (OXPHOS) 68 pathways (Marcais et al., 2014) (Donnelly et al., 2014) (Keating et al., 2016; O'Brien and Finlay, 2019). 69However, the metabolic requirement of NK cells for optimal effector function, in terms of IFN- 70 production, depends on the specific activation stimuli. In particular, receptor mediated activation 71 through anti-NK1.1 and anti-Ly49D in mice appears to require OXPHOS as an essential second signal 72 for IFN- production and appears more susceptible to metabolic inhibition compared to cytokine 73 stimulation ...

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Section: Discussionmentioning

confidence: 99%

IL-15 re-programming compensates for NK cell mitochondrial dysfunction in HIV-1 infection

Cubero

Balint

Alrubayyi³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…70 Because this agonist is capable of activating both CD8+ T and NK cells, there is substantial interest in utilizing ALT-803 in SIV/HIV infection. 72 34 As IL-15 treatment enhances ADCC and can sometimes be used in concert with other cytokines, this approach may also be able to elicit adaptive ΔG NK or cytokine-induced NK cells, though this remains to be shown. This approach may prove pivotal for the development of functional cure therapies for HIV.…”

Section: Blocking Inhibitory Nk Cell Receptors During Infectionmentioning

confidence: 99%

“…Further, ALT‐803 is being tested in concert with other checkpoint inhibitors such as anti‐PD‐1 therapy in patients with metastatic nonsmall cell lung cancer . Because this agonist is capable of activating both CD8+ T and NK cells, there is substantial interest in utilizing ALT‐803 in SIV/HIV infection . Recent work from Garrido et al.…”

Section: Introductionmentioning

confidence: 99%

Adaptive NK cell responses in HIV/SIV infections: A roadmap to cell-based therapeutics?

Ram

Manickam

Lucar

et al. 2019

Journal of Leukocyte Biology

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NK cells play a critical role in antiviral and antitumor responses. Although current NK cell immune therapies have focused primarily on cancer biology, many of these advances can be readily applied to target HIV/simian immunodeficiency virus (SIV)‐infected cells. Promising developments include recent reports that CAR NK cells are capable of targeted responses while producing less off‐target and toxic side effects than are associated with CAR T cell therapies. Further, CAR NK cells derived from inducible pluripotent stem cells or cell lines may allow for more rapid “off‐the‐shelf” access. Other work investigating the IL‐15 superagonist ALT‐803 (now N803) may also provide a recourse for enhancing NK cell responses in the context of the immunosuppressive and inflammatory environment of chronic HIV/SIV infections, leading to enhanced control of viremia. With a broader acceptance of research supporting adaptive functions in NK cells it is likely that novel immunotherapeutics and vaccine modalities will aim to generate virus‐specific memory NK cells. In doing so, better targeted NK cell responses against virus‐infected cells may usher in a new era of NK cell‐tuned immune therapy.

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“…IL-15, in enhancing the survival and also the effector function of HIV specific CD8+ specific lymphocytes which are fundamental for the control of HIV replication [91]. Recent data have shown how the use of IL-15 superagonist ALT-803 is able to invert the trafficking of SIV specific CD8+ cells from peripheral blood to lymph nodes, and in particular inside B cells follicles [92]. Moreover, in rhesus macaques IL-15 superagonist ALT-803 has the ability to increase both NK cells and CD8 + cells with an impact in the reduction of SIV viremia, albeit transiently [93].…”

Section: Immune Therapymentioning

confidence: 99%

Clinical pharmacology in HIV cure research – what impact have we seen?

Giacomelli

Rose

Rusconi

2019

Expert Review of Clinical Pharmacology

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IntroductionCombined antiretroviral therapy (cART) has transformed an inexorably fatal disease into a chronic pathology, shifting the focus of research from the control of viral replication to the possibility of HIV cure. Areas coveredThe present review assesses the principal pharmacological strategies that have been tested for an HIV cure starting from the in vitro proof of concept and the potential rationale of their in vivo applicability. We evaluated the possible pharmacological procedures employed during the early-stage HIV infection and the possibility of cART-free remission. We then analysed the shock and kill approach from the single compounds in vitro mechanism of action, to the in vivo application of single or combined actions. Finally, we briefly considered the novel immunological branch through the discovery and development of broadly neutralizing antibodies in regard of the current and future in vivo therapeutic strategies aiming to verify the clinical applicability of these compounds. Expert opinionDespite an incredible effort in HIV research cure, the likelihood of completely eradicating HIV is unreachable within our current knowledge. A better understanding of the mechanism of viral latency and the fully characterization of HIV reservoir are crucial for the discovery of new therapeutic targets and novel pharmacological entities. KeywordsA c c e p t e d M a n u s c r i p t 3 HIV, eradication, shock and kill, pharmacology.

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The human IL-15 superagonist ALT-803 directs SIV-specific CD8+ T cells into B-cell follicles

Abstract: Key Points IL-15 superagonist sends antiviral CD8 T cells to B-cell follicles, which typically exclude them.

Cited by 77 publications

References 19 publications

IL-15 re-programming compensates for NK cell mitochondrial dysfunction in HIV-1 infection

IL-15 re-programming compensates for NK cell mitochondrial dysfunction in HIV-1 infection

Adaptive NK cell responses in HIV/SIV infections: A roadmap to cell-based therapeutics?

Clinical pharmacology in HIV cure research – what impact have we seen?

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