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1.
Nat Commun ; 11(1): 661, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005826

RESUMO

High dose interleukin-2 (IL-2) is active against metastatic melanoma and renal cell carcinoma, but treatment-associated toxicity and expansion of suppressive regulatory T cells (Tregs) limit its use in patients with cancer. Bempegaldesleukin (NKTR-214) is an engineered IL-2 cytokine prodrug that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2Rß). Here we assess the therapeutic impact and mechanism of action of NKTR-214 in combination with anti-PD-1 and anti-CTLA-4 checkpoint blockade therapy or peptide-based vaccination in mice. NKTR-214 shows superior anti-tumor activity over native IL-2 and systemically expands anti-tumor CD8+ T cells while inducing Treg depletion in tumor tissue but not in the periphery. Similar trends of intratumoral Treg dynamics are observed in a small cohort of patients treated with NKTR-214. Mechanistically, intratumoral Treg depletion is mediated by CD8+ Teff-associated cytokines IFN-γ and TNF-α. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Interleucina-2/análogos & derivados , Melanoma/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Pró-Fármacos/administração & dosagem , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Estudos de Coortes , Quimioterapia Combinada , Feminino , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-2/administração & dosagem , Interleucina-2/agonistas , Interleucina-2/imunologia , Ipilimumab/administração & dosagem , Ativação Linfocitária/efeitos dos fármacos , Melanoma/genética , Melanoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interleucina-2/genética , Receptores de Interleucina-2/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
2.
Nat Commun ; 11(1): 660, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005809

RESUMO

Interleukin-2 (IL-2) is a component of most protocols of adoptive cell transfer (ACT) therapy for cancer, but is limited by short exposure and high toxicities. NKTR-214 is a kinetically-engineered IL-2 receptor ßγ (IL-2Rßγ)-biased agonist consisting of IL-2 conjugated to multiple releasable polyethylene glycol chains resulting in sustained signaling through IL-2Rßγ. We report that ACT supported by NKTR-214 increases the proliferation, homing and persistence of anti-tumor T cells compared to ACT with IL-2, resulting in superior antitumor activity in a B16-F10 murine melanoma model. The use of NKTR-214 increases the number of polyfunctional T cells in murine spleens and tumors compared to IL-2, and enhances the polyfunctionality of T and NK cells in the peripheral blood of patients receiving NKTR-214 in a phase 1 trial. In conclusion, NKTR-214 may have the potential to improve the antitumor activity of ACT in humans through increased in vivo expansion and polyfunctionality of the adoptively transferred T cells.


Assuntos
Transferência Adotiva , Interleucina-2/análogos & derivados , Interleucina-2/agonistas , Melanoma/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Receptores de Interleucina-2/imunologia , Linfócitos T/imunologia , Animais , Humanos , Interleucina-2/administração & dosagem , Interleucina-2/imunologia , Ativação Linfocitária/efeitos dos fármacos , Melanoma/genética , Melanoma/imunologia , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interleucina-2/genética
3.
Chin J Integr Med ; 26(4): 263-269, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31444669

RESUMO

OBJECTIVE: To evaluate whether low-frequency ultrasound-facilitated transdermal delivery of a Chinese medicine (CM) formula could improve the efficacy of intrapleural administration of interleukin-2 (IL-2) in treatment of malignant pleural effusion (MPE). METHODS: A total of 110 eligible participants were randomized into the low-frequency sonophoresis (LFS) of CM (LSF/CM) group (55 cases) and the control group (55 cases) by simple randomization using a random number table. The control group was treated with an intrapleural administration of IL-2; and the LFS/CM group was treated with LFS of a CM gel formulation, combined with the same IL-2 injection as in the control group. The CM formula consisted of Semen Lepidii, Semen Sinapis, Ramulus Cinnamomi, Poriacocos, Herba Lycopi, and Radix Paeoniae Rubra. After 2-week treatment, the therapeutic outcome was determined by the change of the amount of MPE, which was evaluated by B-scan ultrasound and/or chest X-ray, and the change of quality of life (QOL) scores, which were evaluated by the Eastern Cooperative Oncology Group (ECOG) performance status. RESULTS: A significantly higher objective remission rate (ORR) was obtained with intrapleural IL-2 plus LFS/CM than IL-2 treatment alone (P=0.049). In addition, more patients in the LFS/CM group than in the control group had an improved QOL score (P=0.048), and no patients in the LFS/CM group had a reduced QOL. CONCLUSION: LFS of CM formulation could effectively alleviate MPE and improve the QOL of cancer patients.


Assuntos
Imunoterapia , Interleucina-2/administração & dosagem , Medicina Tradicional Chinesa , Derrame Pleural Maligno/tratamento farmacológico , Terapia por Ultrassom , Administração Cutânea , Humanos , Qualidade de Vida
4.
Ann Rheum Dis ; 79(1): 141-149, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31537547

RESUMO

OBJECTIVES: Open-labelled clinical trials suggested that low-dose IL-2 might be effective in treatment of systemic lupus erythematosus (SLE). A double-blind and placebo-controlled trial is required to formally evaluate the safety and efficacy of low-dose IL-2 therapy. METHODS: A randomised, double-blind and placebo-controlled clinical trial was designed to treat 60 patients with active SLE. These patients received either IL-2 (n=30) or placebo (n=30) with standard treatment for 12 weeks, and were followed up for additional 12 weeks. IL-2 at a dose of 1 million IU or placebo was administered subcutaneously every other day for 2 weeks and followed by a 2-week break as one treatment cycle. The primary endpoint was the SLE Responder Index-4 (SRI-4) at week 12. The secondary endpoints were other clinical responses, safety and dynamics of immune cell subsets. RESULTS: At week 12, the SRI-4 response rates were 55.17% and 30.00% for IL-2 and placebo, respectively (p=0.052). At week 24, the SRI-4 response rate of IL-2 group was 65.52%, compared with 36.67% of the placebo group (p=0.027). The primary endpoint was not met at week 12. Low-dose IL-2 treatment resulted in 53.85% (7/13) complete remission in patients with lupus nephritis, compared with 16.67% (2/12) in the placebo group (p=0.036). No serious infection was observed in the IL-2 group, but two in placebo group. Besides expansion of regulatory T cells, low-dose IL-2 may also sustain cellular immunity with enhanced natural killer cells. CONCLUSIONS: Low-dose IL-2 might be effective and tolerated in treatment of SLE. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registries (NCT02465580 and NCT02932137).


Assuntos
Antirreumáticos/uso terapêutico , Interleucina-2/administração & dosagem , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Nefrite Lúpica/tratamento farmacológico , Adulto , Método Duplo-Cego , Feminino , Humanos , Interleucina-2/uso terapêutico , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Resultado do Tratamento , Adulto Jovem
5.
Scand J Immunol ; 90(6): e12822, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31494958

RESUMO

Breaking the balance between effector T cells, including Th17 (T helper cell 17) cells, and regulatory T cells (Tregs) is a key link in the pathogenesis of rheumatic immune diseases, which lead to a new concept of regulating immune balance in the treatment of rheumatic immune diseases. Interleukin (IL)-2 can effectively regulate the differentiation, development and functional activity of regulatory T cells, thus restoring the immune balance between regulatory T cells and effector T cells. Therefore, low-dose IL-2 has been used in the treatment of rheumatic immune diseases, and it has become a promising new choice to achieve therapeutic purpose by regulating the immune balance of T cell. Here, we discuss the role of T cells immune imbalance in the pathogenesis of rheumatic immune diseases and the mechanism of IL-2 in the treatment of rheumatic immune diseases by regulating T cells immune balance and summarize the relevant clinical trials.


Assuntos
Imunomodulação/efeitos dos fármacos , Interleucina-2/uso terapêutico , Doenças Reumáticas/tratamento farmacológico , Doenças Reumáticas/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Animais , Humanos , Interleucina-2/administração & dosagem , Interleucina-2/efeitos adversos , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Resultado do Tratamento
6.
BMC Immunol ; 20(1): 32, 2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484501

RESUMO

BACKGROUND: The development of Systemic lupus erythematosus (SLE) has been associated with the balance of Th17 and Treg cells. IL-2 and rapamycin can influence the populations of both Th17 and Treg cells. However, it is unclear whether low dose of IL-2 and rapamycin can relieve the symptoms of SLE patients and what is the mechanisms. In this study, we aim to analyze the effect of low dose of IL-2 plus rapamycin on the number of Tregs, Th17 cells and the ratio of Th17/Treg cells, as well as to evaluate its therapeutic efficacy in refractory SLE patients. RESULT: Fifty refractory SLE patients and 70 healthy controls were enrolled and followed up for 24 weeks. We found that compared with HC, the refractory SLE patients had a lower number of Tregs, a similar number of Th17 cells, but an increased ratio of Th17/Treg. After the treatment, the number of Tregs of the patients at 12th and 24th week was significantly increased. While the number of Th17 cells was unchanged, the ratio of Th17/Treg was significantly decreased at both 6 weeks and 24 weeks. After 6, 12 and 24 weeks of treatment, the SLEDAI score was significantly reduced. The prednison dosage at 6th,12th and 24th week post treatment was significantly decreased. CONCLUSION: Our results support that the reduction of Tregs and the imbalance of Th17/Treg cells were correlated with the occurrence and development of refractory SLE. Low dose of IL-2 combined with rapamycin was able to restore the number of Tregs and the balance of Th17/Treg cells. As a result, this approach was able to induce immune tolerance and promote disease remission, allowing for the reduction in prednisone dosage. TRIAL REGISTRATION: ChiCTR-IPR-16009451 Registration date: 2016/10/16.


Assuntos
Interleucina-2/farmacologia , Lúpus Eritematoso Sistêmico/imunologia , Sirolimo/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Adulto , Biomarcadores , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Humanos , Interleucina-2/administração & dosagem , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/metabolismo , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Sirolimo/administração & dosagem , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Resultado do Tratamento
7.
Hepatol Int ; 13(5): 573-586, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31172415

RESUMO

BACKGROUND: Switching from nucleos(t)ide analogues to interferon (IFN) improves hepatitis B surface antigen (HBsAg) loss. We aimed to evaluate whether combining immunomodulators such as interleukin-2 (IL-2) and therapeutic vaccine with IFN enhances HBsAg loss in entecavir (ETV)-suppressed patients. METHODS: Ninety-four patients exhibiting virological suppression and hepatitis B e antigen (HBeAg) loss following ETV treatment were randomized 1:1:1 to receive ETV (group I) or IFN (group II) for 48 weeks, or IFN and vaccine for 48 weeks plus IL-2 for 12 weeks (group III). The primary endpoint was HBsAg loss at week 48. Peripheral natural killer (NK) cells and regulatory T cells (Treg) were measured as immune checkpoint indicators. RESULTS: Mean HBsAg decline at week 48 was significantly greater in group III (0.85 log 10 IU/mL) and group II (0.74 log 10 IU/mL), than in group I (0.13 log 10 IU/mL). At week 48, 9.38%, 3.03%, and 3.70% of subjects in group III, II, and I, respectively, achieved HBsAg loss. Among patients with baseline HBsAg titers ranging from 100 to 1500 IU/mL, HBsAg loss rate was 27.3, 7.1, and 0% in group III, II, and I, respectively. Responders in group III showed a significantly higher increase in CD56bright CD16-NK cells from week 24 to 36, and a significant decline in Treg from week 12 to 24 than non-responders. CONCLUSION: For ETV-suppressed patients, particularly those with low baseline HBsAg levels, combination therapy with IFN and other immunomodulators may enhance HBsAg loss, while successful response correlates with partial restoration of NK cells and Tregs.


Assuntos
Antivirais/uso terapêutico , Guanina/análogos & derivados , Vacinas contra Hepatite B/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Interferons/uso terapêutico , Interleucina-2/uso terapêutico , Adulto , Antivirais/administração & dosagem , Terapia Combinada , Quimioterapia Combinada , Feminino , Guanina/uso terapêutico , Antígenos de Superfície da Hepatite B/sangue , Humanos , Interferons/administração & dosagem , Interleucina-2/administração & dosagem , Masculino
8.
Dermatol Ther ; 32(3): e12901, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30974014

RESUMO

The management of metastatic melanoma has been transformed by the development of immune checkpoint inhibitors. However, disease control in patients with extensive locoregional metastases remains a significant challenge. In this context, intralesional interleukin 2 (IL-2) presents a useful therapeutic option to maximize intratumoural drug concentration and minimize systemic toxicity. The utility of combined intralesional IL-2 and systemic immune checkpoint therapy, particularly in loco-regional disease, is unknown. We report the clinical and cellular effects of combined anti-programmed death-1 blockade and intralesional IL-2 therapy in two patients with loco-regional metastatic melanoma. Combined intralesional and systemic therapy induced a lasting resolution of the injected skin tumors; maintained for up to 2 years. This impressive response was associated with increased PD-L1 expression and CD8 T cell infiltration. To our knowledge, this is the first report that raises the possibility of a synergistic effect between intralesional IL-2 and systemic checkpoint inhibition. The lasting remission of injected metastases may be in part due to an altered tumor microenvironment; characterized by increased PD-L1 expression and increased CD8 T cell infiltration. If this interesting and novel preliminary observation is confirmed in larger studies, combined local and systemic immunotherapy could highlight a novel treatment strategy for extensive loco-regional disease.


Assuntos
Interleucina-2/administração & dosagem , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Idoso , Antígeno B7-H1/análise , Humanos , Injeções Intralesionais , Masculino , Melanoma/secundário , Pessoa de Meia-Idade
9.
Am J Physiol Renal Physiol ; 317(5): F1274-F1284, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30892934

RESUMO

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disorder that is characterized by prevalent hypertension, renal injury, and cardiovascular disease. Numerous studies have reported a low prevalence and/or impaired function of regulatory T (TREG) cells in both patients with SLE and murine models of the disease. Evidence suggests that TREG cell dysfunction in SLE results from a deficiency in IL-2. Recent studies have reported that low-dose IL-2 therapy expands TREG cells in mouse models of SLE, but whether expanding TREG cells protects against hypertension and renal injury during SLE is unclear. To examine this question, female SLE (NZBWF1) and control (NZW) mice were injected with vehicle or recombinant mouse IL-2 three times in 24 h followed by single maintenance doses every 5 days for 4 wk. Treatment with IL-2 effectively expanded TREG cell populations in the peripheral blood, spleen, and kidneys. Circulating levels of anti-dsDNA IgG autoantibodies, a marker of SLE disease activity, were higher in SLE mice compared with control mice but were unaffected by IL-2 treatment. As previously reported by our laboratory, mean arterial pressure, measured in conscious mice by a carotid catheter, was higher in SLE mice than in control mice. Mean arterial pressure was significantly lower in IL-2-treated SLE mice compared with vehicle-treated SLE mice, suggesting that expanding TREG cells using low-dose IL-2 attenuates the development of hypertension. While the mechanism for the protection against hypertension is unclear, it does not appear to be related to the delay of SLE disease progression.


Assuntos
Hipertensão/etiologia , Hipertensão/terapia , Interleucina-2/farmacologia , Lúpus Eritematoso Sistêmico/terapia , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Feminino , Interleucina-2/administração & dosagem , Camundongos , Proteínas Recombinantes , Linfócitos T Reguladores/fisiologia
10.
Vet Microbiol ; 230: 49-55, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30827404

RESUMO

Rabbit hemorrhagic disease (RHD) is a highly contagious infection that has caused significant damage to the rabbit industry since 1984. Inactivated vaccines, the currently used prevention measures, are effective in controlling RHD. However, these vaccines are derived from the livers of infected rabbits, which constitutes a major concern in terms of animal welfare and safety. Administration of DNA vaccines in collaboration with appropriate adjuvants, in particular, cytokines, to strengthen the immune response presents a novel optimization strategy to generate more efficient vaccines. In this study, the adjuvant effect of interleukin (IL)-2 co-expression with the VP60 gene in a DNA vaccine was evaluated. In total, four groups of 60 RHD virus (RHDV)-free rabbits (30 days old) were orally or subcutaneously administered recombinant SL7207-pVAX1-IL2-VP60, SL7207-pVAX1-VP60, SL7207-pVAX1 bacteria or the commercial inactive vaccine, and the induced immunity evaluated by challenge with the RHDV(Y8504/China) strain on day 56. The Recombinant SL7207-pVAX1-IL2-VP60 induced a higher level of antibodies than the vaccine SL7207-pVAX1-VP60 and inactivated vaccines to a significant extent. The concentrations of interleukin (IL)-4 were markedly higher than those in groups immunized with the naked or inactive vaccine alone. Furthermore, the fusion gene vaccine provided higher protection (93.33%) after virus challenge relative to immunization with the single gene (SL7207-pVAX1-VP60). The collective results indicate that recombinant SL7207-pVAX1-IL-2-VP60 bacteria exert enhanced protective effects against RHDV and therefore present a strong candidate as a potential vaccine. Moreover, IL-2 enhanced both humoral and cellular responses, highlighting the utility of rabbit IL-2 as an effective adjuvant.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Infecções por Caliciviridae/veterinária , Vírus da Doença Hemorrágica de Coelhos , Interleucina-2/farmacologia , Vacinas de DNA/imunologia , Proteínas Estruturais Virais/genética , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/sangue , Infecções por Caliciviridae/prevenção & controle , Citocinas/sangue , Imunidade Celular , Imunidade Humoral , Imunização , Imunogenicidade da Vacina , Interleucina-2/administração & dosagem , Coelhos , Salmonella typhimurium , Vacinas de DNA/administração & dosagem , Proteínas Estruturais Virais/imunologia , Vacinas Virais/administração & dosagem
11.
Proc Natl Acad Sci U S A ; 116(8): 3100-3105, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30718426

RESUMO

Denileukin diftitox (DAB-IL-2, Ontak) is a diphtheria-toxin-based fusion protein that depletes CD25-positive cells including regulatory T cells and has been approved for the treatment of persistent or recurrent cutaneous T cell lymphoma. However, the clinical use of denileukin diftitox was limited by vascular leak toxicity and production issues related to drug aggregation and purity. We found that a single amino acid substitution (V6A) in a motif associated with vascular leak induction yields a fully active, second-generation biologic, s-DAB-IL-2(V6A), which elicits 50-fold less human umbilical vein endothelial cell monolayer permeation and is 3.7-fold less lethal to mice by LD50 analysis than s-DAB-IL-2. Additionally, to overcome aggregation problems, we developed a production method for the fusion toxin using Corynebacterium diphtheriae that secretes fully folded, biologically active, monomeric s-DAB-IL-2 into the culture medium. Using the poorly immunogenic mouse B16F10 melanoma model, we initiated treatment 7 days after tumor challenge and observed that, while both s-DAB-IL-2(V6A) and s-DAB-IL-2 are inhibitors of tumor growth, the capacity to treat with higher doses of s-DAB-IL-2(V6A) could provide a superior activity window. In a sequential dual-therapy study in tumors that have progressed for 10 days, both s-DAB-IL-2(V6A) and s-DAB-IL-2 given before checkpoint inhibition with anti-programmed cell death-1 (anti-PD-1) antibodies inhibited tumor growth, while either drug given as monotherapy had less effect. s-DAB-IL-2(V6A), a fully monomeric protein with reduced vascular leak, is a second-generation diphtheria-toxin-based fusion protein with promise as a cancer immunotherapeutic both alone and in conjunction with PD-1 blockade.


Assuntos
Toxina Diftérica/administração & dosagem , Interleucina-2/administração & dosagem , Melanoma Experimental/tratamento farmacológico , Receptor de Morte Celular Programada 1/genética , Substituição de Aminoácidos/genética , Anticorpos/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Corynebacterium diphtheriae/química , Corynebacterium diphtheriae/patogenicidade , Toxina Diftérica/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Imunossupressores/administração & dosagem , Imunotoxinas/administração & dosagem , Interleucina-2/química , Subunidade alfa de Receptor de Interleucina-2/efeitos dos fármacos , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Receptores de Interleucina-2/genética , Receptores de Interleucina-2/imunologia , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/química , Linfócitos T Reguladores/efeitos dos fármacos
12.
AIDS Res Hum Retroviruses ; 35(3): 306-309, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30600702

RESUMO

Mucosal-associated invariant T (MAIT) cell populations are reduced in frequency in HIV-1+ patients, and this disruption is associated with systemic immune activation. Reconstitution of MAIT frequency may benefit HIV-1-infected individuals; however, only recently has in vivo work been endeavored. Treatment with interleukin (IL)-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), and recombinant human growth hormone (rhGH) immunotherapy combined with an HIV-1 vaccine in the context of antiretroviral therapy (ART) has shown to reconstitute CD4 T cell population numbers and function. In this study cryopreserved peripheral blood mononuclear cells (PBMCs) from 12 HIV-1+ patients who were undergoing a combination of HIV-1 vaccine and/or IL-2, GM-CSF and rhGH immunotherapy in conjunction with ART were analyzed to assess the potential of this treatment to promote MAIT cell proliferation. PBMCs were thawed from study baseline, weeks 2 and 48 time points, fluorescently stained for MAIT cell markers, and assessed by flow cytometric analysis. Matched pairs and intergroup results were statistically compared using appropriate methods. MAIT cell frequency was increased from baseline at 48 weeks in participants who received vaccine only, whereas individuals receiving IL-2, GM-CSF, and rhGH immunotherapy with or without vaccine did not show additional benefit. Although IL-2, GM-CSF, and rhGH treatment promotes CD4 T cell reconstitution and HIV-1-specific T cell function, it does not support MAIT cell recovery in patients on suppressive ART. Therapeutic immunization however has a positive effect, highlighting the importance of aiming for balanced promotion of T cell population reconstitution to impact on HIV-1 transmission and pathogenesis.


Assuntos
Vacinas contra a AIDS/uso terapêutico , Antirretrovirais/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Soropositividade para HIV/terapia , HIV-1/imunologia , Hormônio do Crescimento Humano/uso terapêutico , Imunização , Interleucina-2/uso terapêutico , Células T Invariáveis Associadas à Mucosa/imunologia , Vacinas contra a AIDS/administração & dosagem , Antirretrovirais/administração & dosagem , Relação CD4-CD8 , Proliferação de Células/efeitos dos fármacos , Estudos de Coortes , Hormônio do Crescimento Humano/administração & dosagem , Humanos , Interleucina-2/administração & dosagem , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico
13.
Cytokine ; 113: 50-60, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29958796

RESUMO

BACKGROUND: Immune tolerance seems to correlate with disease progression and T regulatory cells (Tregs) and myeloid-derived suppressor cells play a relevant role in immunosuppression. Cyclophosphamide (Cyt) and Fluorouracil (FU) seem to reduce these cell populations. METHODS AND OBJECTIVE: Establishing safety, feasibility, activity and impact on the immune system (neutrophil/lymphocyte [N/L], platelet/L [Plt/L], monocyte [M] and lymphocyte subpopulation (CD3, CD4, CD8, CD16, HLADR/CD3, Tregs, cells count), CD8/Treg and C-reactive protein (CRP). TREATMENT: 1) Cyt 300 mg/sqm ±â€¯FU 500 mg/sqm day (d) 1 and interleukin 2 (IL-2) 18 MUI/sqm intravenous (I.V.) d 4-6, 18-20 or 2) Cyt 300 mg/sqm + FU 500 mg/sqm day d 1, IL-2 4.5 MUI subcutaneous (S.C.) d 3-6, 17-20. The cycle was repeated every four weeks for 2 cycles. Stable or responding patients (pts) continued therapy for 3 cycles. RESULTS: From February 2014 to December 2016, 13/14 pre-treated pts (mean 3 lines) with solid tumors were enrolled. Male/Female: 1/1. The median age and Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 68 years and 1 respectively. Mean 2 cycles of therapy were administered. G3-4 toxicities presented as diarrhea and bleeding anemia in 2 pts and proteinuria and erhytroderma in 1pt, respectively. Regarding the hematological profile, a more reduction in Plt, less decrease of Plt/Ly, and less increase of Treg with I.V. than S.C. IL-2 administration was observed. However a transient decrease of Treg on day 7 of first cycle in the I.V. IL-2 was reported. RESPONSE: PR 3 (23%), SD 3 (23%), PD 7 (54%). The response duration was 2+ and 3 months in 2 HCC and 18+ months in the pancreatic cancer (PC). Pathological CR was reported in one HCC treated with I.V. IL-2. The median progression-free-survival (PFS) and overall survival (OS) were 1 and 7 months. CONCLUSION: Cyt-FU-IL-2 can be considered safe, feasible and moderately active in heavily pre-treated pts. Plt, Plt/Ly, CD8/Treg and a transient Tregs reduction were observed without significative difference on survival.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Fluoruracila/uso terapêutico , Interleucina-2/administração & dosagem , Neoplasias/tratamento farmacológico , Idoso , Estudos de Viabilidade , Feminino , Humanos , Infusões Intravenosas/métodos , Injeções Subcutâneas/métodos , Masculino , Uso Off-Label , Intervalo Livre de Progressão
14.
Biomed Pharmacother ; 110: 213-223, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30476722

RESUMO

Sorafenib is a standard targeted drug used to treat hepatocellular carcinoma (HCC). Notably, cytokine has been found to further enhance the therapeutic effectiveness of the targeted drug. Thereby, the aim of this study is to verify whether cytokine IL-2 could increase the anti-cancer effects of sorafenib on liver cancer in vitro. Huh7 cells were used in the present study and the cell apoptosis and migration were determined in response to sorafenib treatment. Then, siRNA and pathway blocker were used to determine the molecular mechanisms by which IL-2 enhance the therapeutic effectiveness of Huh7 liver cancer cell in vitro. The data in our study illustrated that sorafenib treatment induced apoptosis in Huh7 liver cancer cell in vitro, an effect that was accompanied with a drop in cell proliferation and migration. Biological investigation demonstrated that IL-2 supplementation further augmented the pro-apoptotic effects of sorafenib in vitro. At the molecular levels, the combination of IL-2 and sorafenib impaired mitochondrial respiratory function, reduced mitochondrial potential, promoted mitochondrial ROS overloading and activated mitochondrial apoptotic pathway. Meanwhile, we found that IL-2 supplementation induced mitochondrial stress via activating mitochondrial fragmentation in a manner dependent on MAPK-JNK signalling pathway and TAZ protein. Blockade of the JNK signalling pathway and/or knockdown of TAZ could abrogate the inhibitor effects of IL-2/sorafenib on liver cancer survival, growth and mobility. Collectively, these data indicated that IL-2 supplementation could further augment the anti-cancer effectiveness of sorafenib via activating mitochondrial fragmentation in a manner dependent on MAPK-JNK signalling pathway and TAZ protein. This finding identifies mitochondrial stress and the JNK-Hippo pathway as the potential targets to treat liver cancer.


Assuntos
Carcinoma Hepatocelular/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Interleucina-2/administração & dosagem , Neoplasias Hepáticas/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Mitocôndrias/metabolismo , Sorafenibe/administração & dosagem , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Citocinas/administração & dosagem , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos
15.
Ann Rheum Dis ; 78(2): 209-217, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30472651

RESUMO

OBJECTIVE: Regulatory T cells (Tregs) prevent autoimmunity and control inflammation. Consequently, any autoimmune or inflammatory disease reveals a Treg insufficiency. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential. AIM: We aimed to assess this potential and select diseases for further clinical development by cross-investigating the effects of ld-IL2 in a single clinical trial treating patients with 1 of 11 autoimmune diseases. METHODS: We performed a prospective, open-label, phase I-IIa study in 46 patients with a mild to moderate form of either rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet's disease, granulomatosis with polyangiitis, Takayasu's disease, Crohn's disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis. They all received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Patients were evaluated by deep immunomonitoring and clinical evaluation. RESULTS: ld-IL2 was well tolerated whatever the disease and the concomitant treatments. Thorough supervised and unsupervised immunomonitoring demonstrated specific Treg expansion and activation in all patients, without effector T cell activation. Indication of potential clinical efficacy was observed. CONCLUSION: The dose of IL-2 and treatment scheme used selectively activate and expand Tregs and are safe across different diseases and concomitant treatments. This and preliminary indications of clinical efficacy should licence the launch of phase II efficacy trial of ld-IL2 in various autoimmune and inflammatory diseases. TRIAL REGISTRATION NUMBER: NCT01988506.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Fatores Imunológicos/administração & dosagem , Interleucina-2/administração & dosagem , Linfócitos T Reguladores/efeitos dos fármacos , Adulto , Doenças Autoimunes/imunologia , Feminino , Humanos , Fatores Imunológicos/imunologia , Interleucina-2/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Linfócitos T Reguladores/imunologia , Resultado do Tratamento
16.
Arthritis Rheumatol ; 71(4): 632-640, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30407752

RESUMO

OBJECTIVE: To develop a nanoparticle (NP) platform that can expand both CD4+ and CD8+ Treg cells in vivo for the suppression of autoimmune responses in systemic lupus erythematosus (SLE). METHODS: Poly(lactic-co-glycolic acid) (PLGA) NPs encapsulating interleukin-2 (IL-2) and transforming growth factor ß (TGFß) were coated with anti-CD2/CD4 antibodies and administered to mice with lupus-like disease induced by the transfer of DBA/2 T cells into (C57BL/6 × DBA/2)F1 (BDF1) mice. The peripheral frequency of Treg cells was monitored ex vivo by flow cytometry. Disease progression was assessed by measuring serum anti-double-stranded DNA antibody levels by enzyme-linked immunosorbent assay. Kidney disease was defined as the presence of proteinuria or renal histopathologic features. RESULTS: Anti-CD2/CD4 antibody-coated, but not noncoated, NPs encapsulating IL-2 and TGFß induced CD4+ and CD8+ FoxP3+ Treg cells in vitro. The optimal dosing regimen of NPs for expansion of CD4+ and CD8+ Treg cells was determined in in vivo studies in mice without lupus and then tested in BDF1 mice with lupus. The administration of anti-CD2/CD4 antibody-coated NPs encapsulating IL-2 and TGFß resulted in the expansion of CD4+ and CD8+ Treg cells, a marked suppression of anti-DNA antibody production, and reduced renal disease. CONCLUSION: This study shows for the first time that T cell-targeted PLGA NPs encapsulating IL-2 and TGFß can expand both CD4+ and CD8+ Treg cells in vivo and suppress murine lupus. This approach, which enables the expansion of Treg cells in vivo and inhibits pathogenic immune responses in SLE, could represent a potential new therapeutic modality in autoimmune conditions characterized by impaired Treg cell function associated with IL-2 deficiency.


Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Interleucina-2/administração & dosagem , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Nanopartículas/uso terapêutico , Linfócitos T Reguladores/efeitos dos fármacos , Fator de Crescimento Transformador beta/administração & dosagem , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Camundongos Endogâmicos C57BL
17.
Curr Opin Rheumatol ; 31(2): 208-212, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30562181

RESUMO

PURPOSE OF REVIEW: To provide an overview behind the concept and recent advances of low-dose interleukin-2 (IL-2) therapy in systemic lupus erythematosus (SLE). RECENT FINDINGS: A disruption of regulatory T cell homeostasis caused by an acquired deficiency of IL-2 is a crucial event in the pathogenesis of SLE. Here, we highlight the key rationales for the clinical translation of low-dose IL-2 therapy in SLE and summarize the main findings from two independent, early phase uncontrolled clinical studies that investigated the immunological and clinical responses to low-dose IL-2 therapy in patients with active SLE. Important commonalities and differences between these studies with regard to study design and results are discussed. SUMMARY: Low-dose IL-2 therapy is capable to promote the selective expansion of a functionally competent regulatory T cell population in a well-tolerated way and may have the potential to influence the clinical course in patients with active SLE. Although a clearer proof for the clinical efficacy of low-dose IL-2 therapy in SLE is still outstanding, these early studies provide important rationales and the scientific basis for more comprehensive and placebo-controlled trials in the future.


Assuntos
Imunoterapia/métodos , Interleucina-2/administração & dosagem , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Linfócitos T Reguladores/imunologia , Animais , Antineoplásicos/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Resultado do Tratamento
18.
BMC Cancer ; 18(1): 1274, 2018 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-30567529

RESUMO

BACKGROUND: HDIL-2 is approved for advanced melanoma based on its durable antitumor activity. MAGE-A3 cancer immunotherapeutic (MAGE-A3 CI) is a recombinant MAGE-A3 protein combined with an immunostimulant adjuvant system and has shown antitumor activity in melanoma. We assessed the safety and anti-tumor activity of HDIL-2 combined with MAGE-A3 CI in advanced melanoma. METHODS: Patients with unresectable Stage III or Stage IV MAGE-A3-positive melanoma were enrolled in this phase II study. Treatment included an induction phase of MAGE-A3 CI plus HDIL-2 for 8 cycles followed by a maintenance phase of MAGE-A3 CI monotherapy. The primary endpoints were safety and objective response assessed per RECIST v1.1. Immune biomarker and correlative studies on tumor and peripheral blood were performed. RESULTS: Eighteen patients were enrolled. Seventeen patients were evaluable for safety and sixteen for response. Responses occurred in 4/16 (25%) patients with 3 complete responses, and stable disease in 6/16 (38%) patients with a disease control rate of 63%. The median duration of response was not reached at median follow-up of 36.8 months. Induction therapy of HDIL-2 + MAGE-A3 CI had similar toxicities to those reported with HDIL-2 alone. Maintenance MAGE-A3 monotherapy was well-tolerated. Increased immune checkpoint receptor expression by circulating T regulatory cells was associated with poor clinical outcomes; and responders tended to have increased tumor infiltrating T cells in the baseline tumor samples. CONCLUSIONS: The safety profile of HDIL-2 + MAGE-A3 CI was similar to HDIL-2 monotherapy. Maintenance MAGE-A3 CI provides robust anti-tumor activity in patients who achieved disease control with induction therapy. Immune monitoring data suggest that MAGE-A3 CI plus checkpoint inhibitors could be a promising treatment for MAGE-A3-positive melanoma. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01266603 . Registered 12/24/2010, https://clinicaltrials.gov/ct2/show/NCT01266603.


Assuntos
Antígenos de Neoplasias/administração & dosagem , Interleucina-2/administração & dosagem , Melanoma/tratamento farmacológico , Proteínas de Neoplasias/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Adjuvantes Imunológicos , Adulto , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Feminino , Humanos , Imunoterapia , Interleucina-2/genética , Interleucina-2/imunologia , Masculino , Melanoma/genética , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Estadiamento de Neoplasias , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Resultado do Tratamento
19.
Curr Oncol Rep ; 21(1): 1, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30498900

RESUMO

PURPOSE OF REVIEW: Immune checkpoint inhibitors (ICI) are only effective in a subset of patients. Here, we will review the rationale and data supporting the combination of PD-1 pathway inhibition with recombinant cytokines and neoantigen-based cancer vaccines that can potentially increase the number of patients who will benefit from immunotherapy. RECENT FINDINGS: The safety and tolerability of new interleukin(IL)-2 formulations, IL-15 super agonist, and PEGylated IL-10 have been evaluated in early phase clinical trials with promising efficacy data, both as monotherapy and in combination with ICI. Larger studies focusing on the efficacy of these combinations are ongoing. Personalized neoantigen-based cancer vaccines, enabled by improvements in sequencing computational capabilities, have been proven to be feasible, safe, and able to trigger a consistent vaccine-specific immune response in cancer patients. New pharmacologically modified recombinant cytokines and personalized neoantigen-based vaccines may turn these approaches into powerful tools for effective combination immunotherapy.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Vacinas Anticâncer/farmacologia , Citocinas/farmacologia , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Citocinas/genética , Humanos , Interleucina-15/genética , Interleucina-15/farmacologia , Interleucina-2/administração & dosagem , Interleucina-2/análogos & derivados , Interleucina-2/farmacologia , Neoplasias/metabolismo , Neoplasias/terapia , Polietilenoglicóis/farmacologia , Medicina de Precisão/métodos , Receptor de Morte Celular Programada 1/imunologia
20.
Lancet Oncol ; 19(12): 1617-1629, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30442501

RESUMO

BACKGROUND: Immunotherapy with the chimeric anti-GD2 monoclonal antibody dinutuximab, combined with alternating granulocyte-macrophage colony-stimulating factor and intravenous interleukin-2 (IL-2), improves survival in patients with high-risk neuroblastoma. We aimed to assess event-free survival after treatment with ch14.18/CHO (dinutuximab beta) and subcutaneous IL-2, compared with dinutuximab beta alone in children and young people with high-risk neuroblastoma. METHODS: We did an international, open-label, phase 3, randomised, controlled trial in patients with high-risk neuroblastoma at 104 institutions in 12 countries. Eligible patients were aged 1-20 years and had MYCN-amplified neuroblastoma with stages 2, 3, or 4S, or stage 4 neuroblastoma of any MYCN status, according to the International Neuroblastoma Staging System. Patients were eligible if they had been enrolled at diagnosis in the HR-NBL1/SIOPEN trial, had completed the multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide, with or without topotecan, vincristine, and doxorubicin), had achieved a disease response that fulfilled prespecified criteria, had received high-dose therapy (busulfan and melphalan or carboplatin, etoposide, and melphalan) and had received radiotherapy to the primary tumour site. In this component of the trial, patients were randomly assigned (1:1) to receive dinutuximab beta (20 mg/m2 per day as an 8 h infusion for 5 consecutive days) or dinutuximab beta plus subcutaneous IL-2 (6 × 106 IU/m2 per day on days 1-5 and days 8-12 of each cycle) with the minimisation method to balance randomisation for national groups and type of high-dose therapy. All participants received oral isotretinoin (160 mg/m2 per day for 2 weeks) before the first immunotherapy cycle and after each immunotherapy cycle, for six cycles. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT01704716, and EudraCT, number 2006-001489-17, and recruitment to this randomisation is closed. FINDINGS: Between Oct 22, 2009, and Aug 12, 2013, 422 patients were eligible to participate in the immunotherapy randomisation, of whom 406 (96%) were randomly assigned to a treatment group (n=200 to dinutuximab beta and n=206 to dinutuximab beta with subcutaneous IL-2). Median follow-up was 4·7 years (IQR 3·9-5·3). Because of toxicity, 117 (62%) of 188 patients assigned to dinutuximab beta and subcutaneous IL-2 received their allocated treatment, by contrast with 160 (87%) of 183 patients who received dinutuximab beta alone (p<0·0001). 3-year event-free survival was 56% (95% CI 49-63) with dinutuximab beta (83 patients had an event) and 60% (53-66) with dinutuximab beta and subcutaneous IL-2 (80 patients had an event; p=0·76). Four patients died of toxicity (n=2 in each group); one patient in each group while receiving immunotherapy (n=1 congestive heart failure and pulmonary hypertension due to capillary leak syndrome; n=1 infection-related acute respiratory distress syndrome), and one patient in each group after five cycles of immunotherapy (n=1 fungal infection and multi-organ failure; n=1 pulmonary fibrosis). The most common grade 3-4 adverse events were hypersensitivity reactions (19 [10%] of 185 patients in the dinutuximab beta group vs 39 [20%] of 191 patients in the dinutuximab plus subcutaneous IL-2 group), capillary leak (five [4%] of 119 vs 19 [15%] of 125), fever (25 [14%] of 185 vs 76 [40%] of 190), infection (47 [25%] of 185 vs 64 [33%] of 191), immunotherapy-related pain (19 [16%] of 122 vs 32 [26%] of 124), and impaired general condition (30 [16%] of 185 vs 78 [41%] of 192). INTERPRETATION: There is no evidence that addition of subcutaneous IL-2 to immunotherapy with dinutuximab beta, given as an 8 h infusion, improved outcomes in patients with high-risk neuroblastoma who had responded to standard induction and consolidation treatment. Subcutaneous IL-2 with dinutuximab beta was associated with greater toxicity than dinutuximab beta alone. Dinutuximab beta and isotretinoin without subcutaneous IL-2 should thus be considered the standard of care until results of ongoing randomised trials using a modified schedule of dinutuximab beta and subcutaneous IL-2 are available. FUNDING: European Commission 5th Frame Work Grant, St. Anna Kinderkrebsforschung, Fondation ARC pour la recherche sur le Cancer.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Interleucina-2/administração & dosagem , Neuroblastoma/tratamento farmacológico , Adolescente , Fatores Etários , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Interleucina-2/efeitos adversos , Isotretinoína/administração & dosagem , Masculino , Neuroblastoma/imunologia , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Intervalo Livre de Progressão , Fatores de Risco , Fatores de Tempo , Adulto Jovem
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