Low-dose IL-2 selectively activates subsets of CD4+ Tregs and NK cells

Hirakawa, Masahiro; Matos, Tiago R.; Liu, Hongye; Koreth, John; Kim, Haesook T.; Paul, Nicole; Murase, Kazuyuki; Whangbo, Jennifer; Alho, Ana Cristina; Nikiforow, Sarah; Cutler, Corey; Ho, Vincent T.; Armand, Philippe; Alyea, Edwin P.; Antin, Joseph H.; Blazar, Bruce R.; Lacerda, João F.; Soiffer, Robert J.; Ritz, Jérôme

doi:10.1172/jci.insight.89278

Cited by 122 publications

(116 citation statements)

References 65 publications

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“…Evidence of tolerance to sustained cytokine treatment has been previously described for IL-2 and IL-15. 26–29 For comparison, it may be relevant that the FDA-approved dose of IL-2 is given in high-dose pulses that typically yield ongoing—even worsening—symptoms with subsequent treatment cycles. Thus, a crucial goal for future research could be to determine not only optimal dosing but also whether treatment breaks are important.…”

Section: Discussionmentioning

confidence: 99%

ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial

Wrangle

Velcheti

Patel

et al. 2018

The Lancet Oncology

331

290

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Background Immunotherapy with PD-1 or PD-L1 blockade fails to induce a response in about 80% of patients with unselected non-small cell lung cancer (NSCLC), and many of those who do initially respond then develop resistance to treatment. Agonists that target the shared interleukin-2 (IL-2) and IL-15Rβγ pathway have induced complete and durable responses in some cancers, but no studies have been done to assess the safety or efficacy of these agonists in combination with anti-PD-1 immunotherapy. We aimed to define the safety, tolerability, and activity of this drug combination in patients with NSCLC. Methods In this non-randomised, open-label, phase 1b trial, we enrolled patients (aged ≥18 years) with previously treated histologically or cytologically confirmed stage IIIB or IV NSCLC from three academic hospitals in the USA. Key eligibility criteria included measurable disease, eligibility to receive anti-PD-1 immunotherapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received the anti-PD-1 monoclonal antibody nivolumab intravenously at 3 mg/kg (then 240 mg when US Food and Drug Administration [FDA]-approved dosing changed) every 14 days (either as new treatment or continued treatment at the time of disease progression) and the IL-15 superagonist ALT-803 subcutaneously once per week on weeks 1–5 of four 6-week cycles for 6 months. ALT-803 was administered at one of four escalating dose concentrations: 6, 10, 15, or 20 μg/kg. The primary endpoint was to define safety and tolerability and to establish a recommended phase 2 dose of ALT-803 in combination with nivolumab. Analyses were per-protocol and included any patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02523469; phase 2 enrolment of patients is ongoing. Findings Between Jan 18, 2016, and June 28, 2017, 23 patients were enrolled and 21 were treated at four dose levels of ALT-803 in combination with nivolumab. Two patients did not receive treatment because of the development of inter-current illness during enrolment, one patient due to leucopenia and one patient due to pulmonary dysfunction. No dose-limiting toxicities were recorded and the maximum tolerated dose was not reached. The most common adverse events were injection-site reactions (in 19 [90%] of 21 patients) and flu-like symptoms (15 [71%]). The most common grade 3 adverse events, occurring in two patients each, were lymphocytopenia and fatigue. A grade 3 myocardial infarction occurred in one patient. No grade 4 or 5 adverse events were recorded. The recommended phase 2 dose of ALT-803 is 20 μg/kg given once per week subcutaneously in combination with 240 mg intravenous nivolumab every 2 weeks. Interpretation ALT-803 in combination with nivolumab can be safely administered in an outpatient setting. The promising clinical activity observed with the addition of ALT-803 to the regimen of patients with PD-1 monoclonal antibody relapsed and refractory disease shows evidence of anti-tumour act...

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Section: Discussionmentioning

confidence: 99%

ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial

Wrangle

Velcheti

Patel

et al. 2018

The Lancet Oncology

331

290

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“…) increase the proportion and absolute number of circulating Tregs two-to eightfold (17,18), but in mice this increase is observed only following administration of rIL-2/anti-IL-2 antibody complexes (IL-2c) (19). To better model the human setting, we treated mice with a 7-d course of tacrolimus (5 mg/kg) in combination with IL-2c (on days 2, 3, and 4).…”

Section: Il-2 Restores the Cnis-induced Homeostatic Dysfunction Of Trmentioning

confidence: 99%

IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors

Whitehouse

Gray

Mastoridis

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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+ Tregs constitute a heterogeneous lymphocyte subpopulation essential for curtailing effector T cells and establishing peripheral tolerance. Calcineurin inhibitors (CNIs) are among the most effective agents in controlling effector T-cell responses in humans. However, CNIs also reduce the size of the Treg pool. The functional consequences of this negative effect and the mechanisms responsible remain to be elucidated. We report here that CNIs compromise the overall Treg immunoregulatory capacity to a greater extent than would be predicted by the reduction in the size of the Treg compartment, given that they selectively promote the apoptosis of the resting and activated Treg subsets that are known to display the most powerful suppressive function. These effects are caused by reduced access to IL-2, because Tregs remain capable of translocating NFAT even in the presence of high CNI levels. Exogenous IL-2 restores the phenotypic changes and overall gene-expression effects exerted by CNIs and can even promote Treg expansion by enhancing antiapoptotic Bcl-2 expression. In a skin transplant model, the addition of IL-2 synergizes with CNIs treatment, promoting intragraft accumulation of Tregs and prolonged allograft survival. Hence, the combination of IL-2 and CNIs constitutes an optimal immunomodulatory regimen that enhances the pool of suppressive Treg subsets while effectively controlling cytopathic T cells.regulatory T cells | transplantation | IL-2 therapy | calcineurin inhibitors |

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“…IL-2 therapy induced a series of changes in Treg homeostasis, including increased proliferation, increased thymic export, and enhanced resistance to apoptosis [19]. Based on these promising results, a Phase 2 study with low-dose (1 × 10 6 IU/m 2 /day) IL-2 was conducted and elucidated that clinical responders initiated IL-2 significantly earlier (508 versus 917 days after HSCT) and Treg:Tcon ratios ≥ 0.07 at baseline and ≥ 0.2 at week 1 also predicted clinical response [31,32].…”

Section: Therapeutic Intervention In Treg Homeostasis By Low-dose Il-2mentioning

confidence: 99%

Low-dose interleukin-2 as a modulator of Treg homeostasis after HSCT: current understanding and future perspectives

Matsuoka

2017

Int J Hematol

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CD4 + CD25 + Foxp3 + Treg is a functionally distinct subset of mature T cells with broad suppressive activity and has been shown to play an important role in the establishment of immune tolerance after HSCT. Altered cytokine environment in post-HSCT lymphopenia with a relative functional deficiency of IL-2 could hamper the reconstitution of Treg, leading to refractory GVHD. Based on the theory of low-dose IL-2 in which Treg can be selectively stimulated through the high-affinity IL-2 receptor, clinical studies have been conducted and demonstrated that low-dose IL-2 administration can restore Treg homeostasis and promote the expansion of this subset on the polymorphic processes of Treg reconstitution after HSCT. The new therapeutic indication of IL-2 for immune tolerance has launched in the field of HSCT and is spreading to the other fields including the treatment for autoimmune diseases. To further extend the indication of low-dose IL-2 to more patients with various immunological problems, the optimization of the timing and dosing of IL-2 intervention and the concomitant immune suppressive therapy according to each patient-based assessment are to be desired in the near future. Further prospective studies may facilitate the development of novel therapeutic algorithms for the effective and safe induction of immune tolerance after HSCT.

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Low-dose IL-2 selectively activates subsets of CD4+ Tregs and NK cells

Cited by 122 publications

References 65 publications

ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial

ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial

IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors

Low-dose interleukin-2 as a modulator of Treg homeostasis after HSCT: current understanding and future perspectives

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