RESUMEN

Discovered over 4 decades ago in the supernatants of activated T cells, interleukin-2 (IL-2) is a potent pleiotropic cytokine involved in the regulation of immune responses. It is required for effector T cell expansion and differentiation as well as for peripheral tolerance induced by regulatory T cells. High-dose IL-2 treatment was the first FDA-approved immunotherapy for renal cell carcinoma and melanoma, achieving single agent complete and durable responses, albeit only in a small proportion of patients. The therapeutic potential of wild type IL-2 is clinically limited by its short half-life and severe vascular toxicity. Moreover, the activation of regulatory T cells and the terminal differentiation of effector T cells on IL-2 pose additional restrictions. To overcome the toxicity of IL-2 in order to realize its full potential for patients, several novel engineering strategies are being developed and IL-2 based immunotherapy for cancer has emerged as a burgeoning field of clinical and experimental research. In addition, combination of IL-2 with PD-1/L1 pathway blockade shows vastly improved anti-tumor efficacy over either monotherapy in preclinical tumor models. In this review we discuss the biological characteristics of IL-2 and its receptors, as well as its efficacy and treatment limiting toxicities in cancer patients. We also explore the efforts aimed at developing novel and safer IL-2 therapies to harness the full therapeutic potential of this cytokine.

Asunto(s)

Inmunoterapia , Interleucina-2 , Neoplasias , Humanos , Interleucina-2/uso terapéutico , Neoplasias/terapia , Neoplasias/inmunología , Inmunoterapia/métodos , Inmunoterapia/efectos adversos , Animales

RESUMEN

Chimeric antigen receptor (CAR) T cells induce durable responses in patients with refractory hematological tumors. However, low CAR T cell activity, poor engraftment, or short in-patient persistence can lead to tumor progression or relapse. Furthermore, excessive CAR T cell expansion and activation can result in life-threatening cytokine release syndrome (CRS). Thus, in-patient control of the CAR T cell population is essential. Interleukin-2 (IL-2) is a critical cytokine for T cell proliferation and effector function, but its clinical use is limited by immune-mediated toxicity. Here, we report on an orthogonal IL-2 receptor and ligand system that enables specific in vivo control of CAR T cell expansion and activation, wherein an orthogonal human IL-2 (STK-009) selectively pairs with an orthogonal human IL-2Rß (hoRb) expressed on CAR T cells. STK-009 expands hoRb-expressing CAR T cells in the presence and absence of tumor antigen and maintains the presence of stem cell memory T cells (TSCM) and effector T cells. In preclinical models of human CAR-refractory lymphoma, STK-009 treatment resulted in systemic and intratumoral expansion and activation of hoRb-expressing anti­CD19-CD28ζ CAR T cells (SYNCAR). The orthogonal IL-2 receptor/ligand system delivers complete responses in large subcutaneous lymphomas, even with substantially reduced CAR T cell doses, by selectively expanding and activating CAR T cells in vivo. STK-009 withdrawal allowed normal CAR T cell contraction, thereby limiting CRS induced by tumor antigen­specific T cell activation. These data suggest that the orthogonal IL-2 receptor/ligand system provides the in vivo control necessary to maximize efficacy of CAR T therapies.

Asunto(s)

Interleucina-2 , Linfoma , Antígenos CD19 , Humanos , Inmunoterapia Adoptiva , Linfoma/terapia , Recurrencia Local de Neoplasia/terapia , Receptores de Antígenos de Linfocitos T , Linfocitos T

RESUMEN

Background Treatment options for pancreatic ductal adenocarcinoma (PDAC) are limited and checkpoint blockade inhibitors have been disappointing in this disease. Pegilodecakin has demonstrated single agent anti-tumor activity in immune-sensitive tumors. Phase 1 and preclinical data indicate synergy of pegilodecakin with 5-FU and platins. We assessed the safety and activity of pegilodecakin+FOLFOX in patients with PDAC. Methods IVY (NCT02009449) was an open-label phase 1b trial in the United States. Here we report on all enrolled patients from cohort C. Heavily pretreated patients were treated with pegilodecakin (self-administered subcutaneously daily at 2.5, 5, or 10 µg/kg) + 5-flurouracil/leucovorin/oxaliplatin (FOLFOX), dosed per manufacturers prescribing information, until tumor progression. Eligible patients had measurable disease per immune-related response criteria (irRC), were ≥ 18 years of age, and had ECOG performance status of 0 or 1. Patients were evaluated for primary(safety) and secondary (tumor response per irRC) endpoints. Results From 5 August 2014-12 July 2016, 39 patients enrolled in cohort C. All patients were evaluable for safety. In this advanced population, regimen had manageable toxicities with no immune-related adverse events (irAEs) greater than grade 1. The most common grade 3/4/5 TEAEs were thrombocytopenia (21[53.8%] of 39) and anemia (17[43.6%] of 39). In evaluable PDAC patients, the best overall response of pegilodecakin+FOLFOX was 3(14%) with CRs in 2(9%) patients. Conclusions Pegilodecakin+FOLFOX had an acceptable tolerability profile in PDAC, with no substantial irAEs seen, and promising efficacy with the combination yielding a 2-year OS of 24% (95% CI 10-42). These data led to the phase 3 study with pegilodecakin+FOLFOX as second-line therapy of PDAC (SEQUOIA).

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Interleucina-10/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Polietilenglicoles/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/inmunología , Relación Dosis-Respuesta a Droga , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/inmunología , Fluorouracilo/uso terapéutico , Humanos , Interleucina-10/administración & dosificación , Interleucina-10/efectos adversos , Interleucina-10/inmunología , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Leucovorina/inmunología , Leucovorina/uso terapéutico , Persona de Mediana Edad , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/inmunología , Compuestos Organoplatinos/uso terapéutico , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Supervivencia sin Progresión , Criterios de Evaluación de Respuesta en Tumores Sólidos , Neoplasias Pancreáticas

RESUMEN

The expansion and activation of tumor antigen reactive CD8+ T cells are primary goals of immunotherapies for cancer. IL-10 is an anti-inflammatory cytokine with an essential role in the development and proliferation of regulatory T cells, restricting myeloid and chronic inflammatory T cell responses. However, IL-10 is also essential for the expansion of antigen activated, tumor specific CD8+ T cells, leading to spontaneous tumor development in IL-10 deficient patients and mice. IL-10 induces IFNγ and cytotoxic mediators in antigen activated T cells. In clinical trials, monotherapy with recombinant, pegylated IL-10 (Pegilodecakin) induced objective responses in cancer patients. Patients receiving pegilodecakin had a systemic increase of IFNγ and granzymes, proliferation and expansion of immune checkpoint positive CD8+ T cells. Combination of pegilodecakin with anti-PD-1 appeared to improve on the efficacy of the single agents.

Asunto(s)

Linfocitos T CD8-positivos/inmunología , Interleucina-10/inmunología , Neoplasias/inmunología , Receptores Toll-Like/inmunología , Animales , Humanos , Inflamación/inmunología , Interleucina-10/agonistas , Interleucina-10/genética , Interleucina-10/uso terapéutico , Neoplasias/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico

RESUMEN

BACKGROUND: IL-10 has anti-inflammatory and CD8+ T-cell stimulating activities. Pegilodecakin (pegylated IL-10) is a first-in-class, long-acting IL-10 receptor agonist that induces oligoclonal T-cell expansion and has single-agent activity in advanced solid tumours. We assessed the safety and activity of pegilodecakin with anti-PD-1 monoclonal antibody inhibitors in patients with advanced solid tumours. METHODS: We did a multicentre, multicohort, open-label, phase 1b trial (IVY) at 12 cancer research centres in the USA. Patients were assigned sequentially into cohorts. Here, we report on all enrolled patients from two cohorts treated with pegilodecakin combined with anti-PD-1 inhibitors. Eligible patients were aged at least 18 years with histologically or cytologically confirmed advanced malignant solid tumours refractory to previous therapies, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with uncontrolled infectious diseases were excluded. Pegilodecakin was provided in single-use 3 mL vials and was self-administered subcutaneously by injection at home at 10 µg/kg or 20 µg/kg once per day in combination with pembrolizumab (2 mg/kg every 3 weeks or 200 mg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks or 240 mg every 2 weeks or 480 mg every 4 weeks at the approved dosing), both of which were given intravenously at the study site. Patients received pembrolizumab or nivolumab with pegilodecakin until disease progression, toxicity necessitating treatment discontinuation, patient withdrawal of consent, or study end. The primary endpoints were safety and tolerability, assessed in all patients enrolled in the study who received any amount of study medication including at least one dose of pegilodecakin, and pharmacokinetics (previously published). Secondary endpoints included objective response by immune-related response criteria in all patients who were treated and had evaluable measurements. The study is active but no longer recruiting, and is registered with ClinicalTrials.gov, NCT02009449. FINDINGS: Between Feb 13, 2015, and Sept 12, 2017, 111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer. Data cutoff was July 1, 2018. Median follow-up was 26·9 months (IQR 22·3-31·5) for patients with non-small-cell lung cancer, 33·0 months (29·2-35·1) for those with melanoma, and 22·7 months (20·9-27·0) for those with renal cell carcinoma. At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma). INTERPRETATION: In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma. FUNDING: ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company.

Asunto(s)

Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Interleucina-10/administración & dosificación , Neoplasias/tratamiento farmacológico , Nivolumab/administración & dosificación , Polietilenglicoles/administración & dosificación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Humanos , Interleucina-10/efectos adversos , Interleucina-10/farmacocinética , Masculino , Persona de Mediana Edad , Neoplasias/inmunología , Neoplasias/patología , Nivolumab/efectos adversos , Polietilenglicoles/efectos adversos , Polietilenglicoles/farmacocinética , Receptor de Muerte Celular Programada 1/inmunología , Estados Unidos

RESUMEN

Anemia in cancer patients is associated with poor quality of life, reduced response to therapy, and decreased overall survival. We describe a case of a 56-year old woman with advanced metastatic non-small cell lung carcinoma who demonstrated marked response to a novel combinational immunotherapy approach involving a long-acting PEGylated construct of recombinant human Interleukin-10 with Nivolumab, an anti-PD-L1 checkpoint inhibitor. While on treatment, the patient developed severe anemia and hyper-ferritinemia requiring RBC transfusion support. Here we discuss a possible novel immune mechanism of IL10-mediated anemia in correlation with tumor response.

RESUMEN

PURPOSE OF REVIEW: Interleukin-10 (IL-10) is a cytokine with anti-inflammatory properties, which induces activation and proliferation of antigen-activated intratumoral CD8+ T cells. This review discusses the evolution of pegylated IL-10 (pegilodecakin) from preclinical investigation through first-in-human studies in oncology. RECENT FINDINGS: Pegilodecakin was evaluated across multiple advanced solid tumors in a large phase 1/1b trial alone and in combination with chemotherapy or anti-PD-1 antibodies. Pegilodecakin monotherapy had immunologic and clinical activity in renal cell carcinoma (RCC) and uveal melanoma. In combination with anti-PD-1 inhibitors, pegilodecakin increased the responses in RCC and lung cancer with efficacy agnostic to PD-L1 status and tumor mutational burden. Pegilodecakin with FOLFOX had activity in pretreated pancreatic cancer, instructing the ongoing randomized phase III trial of the combination versus FOLFOX. The increased half-life of pegilodecakin enabled compelling preclinical data for IL-10 which has now been confirmed by clinical activity in a variety of cancers. The ability of pegilodecakin to both exert anti-tumor immunity and inhibit tumor-associated inflammation characterizes the uniqueness of this cytokine therapy.

Asunto(s)

Interleucina-10/uso terapéutico , Neoplasias/tratamiento farmacológico , Polietilenglicoles/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Animales , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase III como Asunto , Evaluación Preclínica de Medicamentos , Humanos , Inmunoterapia/métodos , Interleucina-10/inmunología , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Ensayos Clínicos Controlados Aleatorios como Asunto

RESUMEN

Tumor-reactive T cell exhaustion prevents the success of immune therapies. Pegilodecakin activates intratumoral CD8+ T cells in mice and induces objective tumor responses in patients. Here we report that pegilodecakin induces hallmarks of CD8+ T cell immunity in cancer patients, including elevation of interferon-γ and GranzymeB, expansion and activation of intratumoral CD8+ T cells, and proliferation and expansion of LAG-3+ PD-1+ CD8+ T cells. On pegilodecakin, newly expanded T cell clones, undetectable at baseline, become 1%-10% of the total T cell repertoire in the blood. Elevation of interleukin-18, expansion of LAG-3+ PD-1+ T cells and novel T cell clones each correlated with objective tumor responses. Combined pegilodecakin with anti-PD-1 increased the expansion of LAG-3+ PD-1+ CD8+ T cells.

Asunto(s)

Antineoplásicos/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Inmunoterapia/métodos , Interleucina-10/farmacología , Activación de Linfocitos/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias/inmunología , Polietilenglicoles/uso terapéutico , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Granzimas/sangre , Humanos , Interferón gamma/sangre , Interleucina-10/química , Interleucina-10/uso terapéutico , Interleucina-18/metabolismo , Ratones , Ratones Endogámicos C57BL , Neoplasias/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores

RESUMEN

Purpose Interleukin-10 (IL-10) stimulates the expansion and cytotoxicity of tumor-infiltrating CD8+ T cells and inhibits inflammatory CD4+ T cells. Pegylation prolongs the serum concentration of IL-10 without changing the immunologic profile. This phase I study sought to determine the safety and antitumor activity of AM0010. Patients and Methods Patients with selected advanced solid tumors were treated with AM0010 in a dose-escalation study, which was followed by a renal cell cancer (RCC) dose-expansion cohort. AM0010 was self-administered subcutaneously at doses of 1 to 40 µg/kg once per day. Primary end points were safety and tolerability; clinical activity and immune activation were secondary end points. Results In the dose-escalation and -expansion cohorts, 33 and 18 patients, respectively, were treated with daily subcutaneous injection of AM0010. AM0010 was tolerated in a heavily pretreated patient population. Treatment-related adverse events (AEs) included anemia, fatigue, thrombocytopenia, fever, and injection site reactions. Grade 3 to 4 nonhematopoietic treatment-related AEs, including rash (n = 2) and transaminitis (n = 1), were observed in five of 33 patients. Grade 3 to 4 anemia or thrombocytopenia was observed in five patients. Most treatment-related AEs were transient or reversible. AM0010 led to systemic immune activation with elevated immune-stimulatory cytokines and reduced transforming growth factor beta in the serum. Partial responses were observed in one patient with uveal melanoma and four of 15 evaluable patients with RCC treated at 20 µg/kg (overall response rate, 27%). Prolonged stable disease of at least 4 months was observed in four patients, including one with colorectal cancer with disease stabilization for 20 months. Conclusion AM0010 has an acceptable toxicity profile with early evidence of antitumor activity, particularly in RCC. These data support the further evaluation of AM0010 both alone and in combination with other immune therapies and chemotherapies.

Asunto(s)

Citocinas/sangre , Interleucina-10/efectos adversos , Neoplasias/tratamiento farmacológico , Polietilenglicoles/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Anemia/inducido químicamente , Carcinoma de Células Renales/tratamiento farmacológico , Erupciones por Medicamentos/etiología , Exantema/inducido químicamente , Fatiga/inducido químicamente , Femenino , Fiebre/inducido químicamente , Humanos , Inyecciones Subcutáneas/efectos adversos , Interferón gamma/sangre , Interleucina-10/inmunología , Interleucina-10/farmacocinética , Interleucina-10/uso terapéutico , Interleucina-4/sangre , Interleucina-8/sangre , Neoplasias Renales/tratamiento farmacológico , Masculino , Melanoma/tratamiento farmacológico , Persona de Mediana Edad , Neoplasias/patología , Polietilenglicoles/farmacocinética , Polietilenglicoles/uso terapéutico , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapéutico , Trombocitopenia/inducido químicamente , Factor de Crecimiento Transformador beta/sangre , Neoplasias de la Úvea/tratamiento farmacológico , Adulto Joven

RESUMEN

Interleukin-10 (IL-10) is a multifunctional cytokine that exerts potent context specific immunostimulatory and immunosuppressive effects. We have investigated the mechanism by which PEGylated rIL-10 regulates plasma cholesterol in mice and humans. In agreement with previous work on rIL-10, we report that PEGylated rIL-10 harnesses the myeloid immune system to control total plasma cholesterol levels. We have discovered that PEG-rMuIL-10's dramatic lowering of plasma cholesterol is dependent on phagocytotic cells. In particular, PEG-rHuIL-10 enhances cholesterol uptake by Kupffer cells. In addition, removal of phagocytotic cells dramatically increases plasma cholesterol levels, suggesting for the first time that immunological cells are implicitly involved in regulating total cholesterol levels. These data suggest that treatment with PEG-rIL-10 potentiates endogenous cholesterol regulating cell populations not currently targeted by standard of care therapeutics. Furthermore, we show that IL-10's increase of Kupffer cell cholesterol phagocytosis is concomitant with decreases in liver cholesterol and triglycerides. This leads to the reversal of early periportal liver fibrosis and facilitates the restoration of liver health. These data recommend PEG-rIL-10 for evaluation in the treatment of fatty liver disease and preventing its progression to non-alcoholic steatohepatitis. In direct confirmation of our in vivo findings in the treatment of hypercholesterolemic mice with PEG-rMuIL-10, we report that treatment of hypercholesterolemic cancer patients with PEG-rHuIL-10 lowers total plasma cholesterol by up to 50%. Taken together these data suggest that PEG-rIL-10's cholesterol regulating biology is consistent between mice and humans.

Asunto(s)

Colesterol/sangre , Hipercolesterolemia/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Interleucina-10/uso terapéutico , Macrófagos del Hígado/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Colesterol/inmunología , Femenino , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/inmunología , Factores Inmunológicos/química , Factores Inmunológicos/farmacología , Interleucina-10/química , Interleucina-10/farmacología , Macrófagos del Hígado/inmunología , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Polietilenglicoles/química , Polietilenglicoles/farmacología , Polietilenglicoles/uso terapéutico , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Adulto Joven

RESUMEN

Interleukin-10 (IL-10) exerts both immunosuppressive and immunostimulatory effects. While the immunosuppressive effects are widely known, it has only been recently reported that pegylated recombinant human IL-10 (PEG-rHuIL-10) elicits potent interferon-γ (IFN-γ) and CD8 T-cell-dependent antitumor effects in murine tumor models. In this study, we show that PEG-rHuIL-10 exerts immune inhibitory effects on human peripheral blood mononuclear cell (PBMC) bulk cultures and stimulatory effects in CD8 T cells within the same culture. Also, in isolated CD8 T cells, PEG-rHuIL-10 potentiates prototypic Tc1 cytokine IFN-γ expression and induces perforin and granzyme B secretion. IFN-γ and granzyme B secretion is dependent on T-cell receptor ligation and is therefore not indiscriminately released by PEG-rHuIL-10 treatment. STAT3, NF-κB, AP1, and MEK inhibition blocks IFN-γ potentiation, while perforin induction is impeded by AP1 inhibition, and granzyme B induction is blocked by both AP1 and MEK inhibition. These results extend previous pegylated IL-10 preclinical findings to human CD8 T cells and implicate a strong degree of translation for pegylated IL-10 use in cancer therapy.

Asunto(s)

Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/fisiología , Citotoxicidad Inmunológica/efectos de los fármacos , Interferón gamma/biosíntesis , Interleucina-10/farmacología , Células Cultivadas , Granzimas/metabolismo , Humanos , Perforina/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Proteínas Recombinantes/farmacología , Transducción de Señal/efectos de los fármacos

RESUMEN

Human cancer is characterized by deficits in antigen-specific immunity and intratumoral CD8(+) T cells. On the other hand, inflammatory macrophages and mediators of chronic inflammation are highly prevalent in patients with late-stage cancer. Intratumoral T-cell deficiency and chronic inflammation have been linked independently to a poor prognosis in patients with cancer, and therapeutic approaches to overcome either pathology separately are in clinical testing. The anti-inflammatory cytokine interleukin (IL)-10 suppresses macrophage and proinflammatory Th17 T-cell responses by inhibiting the inflammatory cytokines IL-6 and IL-12/23. Corroborating the anti-inflammatory action of IL-10, deficiency in IL-10 leads to a stimulation of inflammatory responses and inflammatory bowel disease. The anti-inflammatory role of IL-10 fostered the assumption that IL-10 undermines the immune response to cancer. However, mice and humans deficient in IL-10 signaling develop tumors spontaneously and at high rates. Overexpression of IL-10 in models of human cancer or treatment with a pegylated IL-10 (PEG-IL-10) led to tumor rejection and long-lasting tumor immunity. IL-10 stimulates cytotoxicity of CD8(+) T cells and the expression of IFN-γ in CD8(+) T cells. IL-10-induced tumor rejections are dependent on the expression of IFN-γ and granzymes in tumor-resident CD8(+) T cells and the upregulation of MHC molecules. These findings reconcile earlier clinical data, which showed that recombinant IL-10 increased IFN-γ and granzymes in the blood of treated individuals. PEG-IL-10 is therefore a unique therapeutic agent, which simultaneously stimulates antitumor immunity and inhibits tumor-associated inflammation.

Asunto(s)

Linfocitos T CD8-positivos/metabolismo , Inflamación/complicaciones , Inflamación/inmunología , Interleucina-10/inmunología , Neoplasias/inmunología , Animales , Regulación Neoplásica de la Expresión Génica , Granzimas/metabolismo , Humanos , Interferón gamma/metabolismo , Interleucina-10/uso terapéutico , Macrófagos/inmunología , Ratones , Neoplasias/tratamiento farmacológico , Polietilenglicoles/farmacología , Transducción de Señal , Células Th17/inmunología

Asunto(s)

Subunidad alfa del Receptor de Interleucina-10/deficiencia , Subunidad alfa del Receptor de Interleucina-10/genética , Subunidad beta del Receptor de Interleucina-10/deficiencia , Subunidad beta del Receptor de Interleucina-10/genética , Linfoma de Células B/genética , Linfoma de Células B/inmunología , Femenino , Humanos , Masculino

RESUMEN

Recently, the development of several strategies based on immunotherapy has raised hopes for a more promising way to treat cancer patients. Here, we describe how interleukin (IL)-10, a seemingly unlikely candidate, stimulates the immune system in a particularly efficacious way. IL-10, an omnipotent anti-inflammatory cytokine, delivers an equally potent immune stimulation in the context of CD8(+) T cells and tumor immunity. By activation of tumor-resident, tumor-specific CD8(+) T cells, pegylated IL-10 can induce rejection of large and metastasizing tumors in mice. Here, we summarize the mechanisms of action of IL-10, the reasons why the mechanisms may be crucial for the treatment of cancer patients, and the rationale for applying pegylated IL-10 in the clinic.

Asunto(s)

Linfocitos T CD8-positivos/metabolismo , Interferón gamma/metabolismo , Interleucina-10/farmacología , Polietilenglicoles/farmacología , Animales , Linfocitos T CD8-positivos/inmunología , Modelos Animales de Enfermedad , Humanos , Inmunoterapia/métodos , Interferón gamma/inmunología , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/terapia

RESUMEN

Interleukin-10 (IL-10) is considered to be an immunosuppressive cytokine. However, the continuous administration of pegylated IL-10 (PEG-IL10) leads to the rejection of large, firmly established and metastatic syngeneic tumors. PEG-IL10 therapy induces the expansion and activation of intratumoral, tumor antigen-specific CD8(+) T cells, leading to interferon γ (IFNγ)-mediated Th1 like immunity and tumor rejection.

RESUMEN

Successful cancer immunotherapy is thought to require de novo priming of tumor specific CD8(+) T cells in lymphatic organs. Contrasting these beliefs, cancer therapy based on interleukin-10 (IL-10) results in tumor rejection without a requirement for T-cell trafficking from lymphatic organs. Rather, IL-10 directly activates autochthonous, tumor-resident CD8(+) T cells.

RESUMEN

The role of regulatory T cells (T(regs)) in human colon cancer (CC) remains controversial: high densities of tumor-infiltrating T(regs) can correlate with better or worse clinical outcomes depending on the study. In mouse models of cancer, T(regs) have been reported to suppress inflammation and protect the host, suppress T cells and protect the tumor, or even have direct cancer-promoting attributes. These different effects may result from the presence of different T(reg) subsets. We report the preferential expansion of a T(reg) subset in human CC with potent T cell-suppressive, but compromised anti-inflammatory, properties; these cells are distinguished from T(regs) present in healthy donors by their coexpression of Foxp3 and RORγt. T(regs) with similar attributes were found to be expanded in mouse models of hereditary polyposis. Indeed, ablation of the RORγt gene in Foxp3(+) cells in polyp-prone mice stabilized T(reg) anti-inflammatory functions, suppressed inflammation, improved polyp-specific immune surveillance, and severely attenuated polyposis. Ablation of interleukin-6 (IL-6), IL-23, IL-17, or tumor necrosis factor-α in polyp-prone mice reduced polyp number but not to the same extent as loss of RORγt. Surprisingly, loss of IL-17A had a dual effect: IL-17A-deficient mice had fewer polyps but continued to have RORγt(+) T(regs) and developed invasive cancer. Thus, we conclude that RORγt has a central role in determining the balance between protective and pathogenic T(regs) in CC and that T(reg) subtype regulates inflammation, potency of immune surveillance, and severity of disease outcome.

Asunto(s)

Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Linfocitos T Reguladores/inmunología , Proteína de la Poliposis Adenomatosa del Colon/metabolismo , Animales , Proliferación Celular , Citocinas/metabolismo , Factores de Transcripción Forkhead/metabolismo , Humanos , Vigilancia Inmunológica , Terapia de Inmunosupresión , Inflamación/patología , Pólipos Intestinales/inmunología , Pólipos Intestinales/patología , Pólipos Intestinales/prevención & control , Ratones , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/deficiencia , Células Th17/inmunología

RESUMEN

The presence of activated intratumoral T cells correlates clinically with better prognosis in patients with cancer. Although tumor vaccines can increase the number of tumor-specific CD8(+) T cells in systemic circulation, they frequently fail to increase the number of active and tumor reactive T cells within the tumor. Here we show that treatment with the pleiotropic cytokine interleukin-10 (IL-10) induces specific activation of tumor-resident CD8(+) T cells as well as their intratumoral expansion in several mouse tumor models. We found that inhibition of T-cell trafficking from lymphoid organs did not impair IL-10-induced tumor rejection or the activation of tumor-resident CD8(+) T cells. Tumor-resident CD8(+) T cells expressed elevated levels of the IL-10 receptor and were directly activated by IL-10, resulting in prominent phosphorylation of STAT3 and STAT1. Although CD4(+) T cells, regulatory T cells, NK cells, and dendritic cells have been reported as prominent targets of IL-10 in the tumor microenvironment, we found that expression of the IL-10R was required only on CD8(+) T cells to facilitate IL-10-induced tumor rejection as well as in situ expansion and proliferation of tumor-resident CD8 T cells. Together, our findings indicate that IL-10 activates CD8(+) T-cell-mediated tumor control and suggest that IL-10 may represent a potential tumor immunotherapy in human patients with cancer.

Asunto(s)

Linfocitos T CD8-positivos/inmunología , Interleucina-10/farmacología , Activación de Linfocitos/inmunología , Neoplasias/inmunología , Animales , Femenino , Humanos , Sistema Linfático/inmunología , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Receptores de Interleucina-10/metabolismo , Linfocitos T Reguladores/inmunología

RESUMEN

Tumor immune surveillance and cancer immunotherapies are thought to depend on the intratumoral infiltration of activated CD8(+) T cells. Intratumoral CD8(+) T cells are rare and lack activity. IL-10 is thought to contribute to the underlying immune suppressive microenvironment. Defying those expectations we demonstrate that IL-10 induces several essential mechanisms for effective antitumor immune surveillance: infiltration and activation of intratumoral tumor-specific cytotoxic CD8(+) T cells, expression of the Th1 cytokine interferon-γ (IFNγ) and granzymes in CD8(+) T cells, and intratumoral antigen presentation molecules. Consequently, tumor immune surveillance is weakened in mice deficient for IL-10 whereas transgenic overexpression of IL-10 protects mice from carcinogenesis. Treatment with pegylated IL-10 restores tumor-specific intratumoral CD8(+) T cell function and controls tumor growth.

Asunto(s)

Interferón gamma/metabolismo , Interleucina-10/metabolismo , Neoplasias Experimentales/inmunología , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/metabolismo , Linfocitos T CD8-positivos/enzimología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Citotoxicidad Inmunológica , Femenino , Granzimas/metabolismo , Humanos , Interferón gamma/genética , Interleucina-10/genética , Interleucina-10/inmunología , Subunidad alfa del Receptor de Interleucina-10/genética , Subunidad alfa del Receptor de Interleucina-10/metabolismo , Neoplasias Mamarias Experimentales/irrigación sanguínea , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Trasplante de Neoplasias , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Perforina/metabolismo , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Bazo/metabolismo , Trasplante Heterólogo , Carga Tumoral , Escape del Tumor

RESUMEN

Tumor immune surveillance and CD8+ T cells in particular appear capable of recognizing the antigenic properties of human tumor cells. However, those antigen specific T cells are often excluded from tumor tissue or are functionally limited in their cytotoxic capacity. Instead, the immune response provides proinflammatory cytokines and proteases promoting tumor growth and progression while subverting cytotoxic anti-tumor immunity. The cytokines and the inflammatory mechanisms driving tumor associated inflammation resemble tissue remodeling processes during wound healing and chronic inflammatory diseases. In this chapter, we summarize the current knowledge of how inflammatory cytokines may promote the deviation of anti-tumor immunity toward a tumor promoting, noncytotoxic inflammation.

Asunto(s)

Neoplasias/inmunología , Inmunidad Adaptativa , Citocinas/fisiología , Humanos , Vigilancia Inmunológica , Linfocitos T/inmunología