RESUMEN
PURPOSE: Bempegaldesleukin (BEMPEG) is a pegylated interleukin (IL)-2 cytokine prodrug engineered to provide controlled and sustained activation of the clinically validated IL-2 pathway, with the goal of preferentially activating and expanding effector CD8+ T cells and natural killer cells over immunosuppressive regulator T cells in the tumor microenvironment. The open-label, phase III randomized controlled PIVOT-09 trial investigated the efficacy and safety of BEMPEG plus nivolumab (NIVO) as first-line treatment for advanced/metastatic clear cell renal cell carcinoma (ccRCC) with intermediate-/poor-risk disease. METHODS: Patients with previously untreated advanced/metastatic ccRCC were randomly assigned (1:1) to BEMPEG plus NIVO, or investigator's choice of tyrosine kinase inhibitor (TKI; sunitinib or cabozantinib). Coprimary end points were objective response rate (ORR) by blinded independent central review and overall survival (OS) in patients with International Metastatic RCC Database Consortium (IMDC) intermediate-/poor-risk disease. RESULTS: Overall, 623 patients were randomly assigned to BEMPEG plus NIVO (n = 311) or TKI (n = 312; sunitinib n = 225, cabozantinib n = 87), of whom 514 (82.5%) had IMDC intermediate-/poor-risk disease. In patients with IMDC intermediate-/poor-risk disease, ORR with BEMPEG plus NIVO versus TKI was 23.0% (95% CI, 18.0 to 28.7) versus 30.6% (95% CI, 25.1 to 36.6; difference, -7.7 [95% CI, -15.2 to -0.2]; P = .0489), and median OS was 29.0 months versus not estimable (hazard ratio, 0.82 [95% CI, 0.61 to 1.10]; P = .192), respectively. More frequent all-grade treatment-related adverse events (TRAEs) with BEMPEG plus NIVO versus TKI included pyrexia (32.6% v 2.0%) and pruritus (31.3% v 8.8%). Grade 3/4 TRAEs were less frequent with BEMPEG plus NIVO (25.8%) versus TKI (56.5%). CONCLUSION: First-line BEMPEG plus NIVO for advanced/metastatic ccRCC did not improve efficacy in patients with intermediate-/poor-risk disease but led to fewer grade 3/4 TRAEs versus TKI.
Asunto(s)
Anilidas , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renales , Neoplasias Renales , Nivolumab , Polietilenglicoles , Piridinas , Sunitinib , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Anilidas/administración & dosificación , Anilidas/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Femenino , Masculino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Nivolumab/administración & dosificación , Nivolumab/uso terapéutico , Nivolumab/efectos adversos , Anciano , Piridinas/administración & dosificación , Piridinas/uso terapéutico , Sunitinib/uso terapéutico , Sunitinib/administración & dosificación , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Adulto , Interleucina-2/administración & dosificación , Interleucina-2/uso terapéutico , Interleucina-2/efectos adversos , Interleucina-2/análogos & derivados , Anciano de 80 o más AñosRESUMEN
Bempegaldesleukin (BEMPEG: NKTR-214) is an immunostimulatory IL-2 cytokine prodrug engineered to deliver a controlled, sustained and preferential IL-2 pathway signal. Nivolumab (NIVO), a PD-1 inhibitor, has been shown to prolong survival in patients with advanced melanoma and recurrence-free survival in the adjuvant setting. PIVOT-02 showed that BEMPEG plus NIVO was well-tolerated and demonstrated clinical activity as first-line therapy in metastatic melanoma. PIVOT-12 is a randomized, phase III, global, multicenter, open-label study comparing adjuvant therapy with BEMPEG plus NIVO versus NIVO alone in adult and adolescent patients with completely resected cutaneous stage III/IV melanoma at high risk of recurrence. The primary objective is to compare the efficacy, as measured by recurrence-free survival, of BEMPEG plus NIVO versus NIVO.
Following surgery, patients with advanced melanoma may require further treatment to reduce the likelihood of disease recurrence. Nivolumab (NIVO), a checkpoint inhibitor, reduces the risk of melanoma recurrence by enhancing the ability of the immune system to fight disease. Despite the availability of NIVO and other therapies, many patients with melanoma still experience disease recurrence after surgery. This article presents information on a clinical trial named PIVOT-12, which aims to assess the effectiveness of a new investigational drug called bempegaldesleukin that modifies the immune system and is given with NIVO to patients with stage III/IV melanoma following surgery. The main end point being measured is recurrence-free survival, which measures the time between a patient starting the study and the date of disease recurrence. Clinical Trial Registration: NCT04410445 (ClinicalTrials.gov).
Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Interleucina-2/análogos & derivados , Interleucina-2/agonistas , Melanoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Nivolumab/uso terapéutico , Polietilenglicoles/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Adyuvantes Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Supervivencia sin Enfermedad , Humanos , Infusiones Intravenosas , Interleucina-2/administración & dosificación , Interleucina-2/uso terapéutico , Melanoma/mortalidad , Melanoma/secundario , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Nivolumab/administración & dosificación , Polietilenglicoles/administración & dosificación , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Resultado del TratamientoRESUMEN
BACKGROUND: Atherosclerosis is a chronic inflammatory disease of the artery wall. Regulatory T cells (Tregs) limit inflammation and promote tissue healing. Low doses of interleukin (IL)-2 have the potential to increase Tregs, but its use is contraindicated for patients with ischemic heart disease. METHODS: In this randomized, double-blind, placebo-controlled, dose-escalation trial, we tested low-dose subcutaneous aldesleukin (recombinant IL-2), given once daily for 5 consecutive days. In study part A, the primary end point was safety, and patients with stable ischemic heart disease were randomly assigned to receive placebo or to one of five dose groups (range, 0.3 to 3.0 × 106 IU daily). In study part B, patients with acute non-ST elevation myocardial infarction or unstable angina were randomly assigned to receive placebo or to one of two dose groups (1.5 and 2.5 × 106 IU daily). The coprimary end points were safety and the dose required to increase circulating Tregs by 75%. Single-cell RNA-sequencing of circulating immune cells was used to provide a mechanistic assessment of the effects of aldesleukin. RESULTS: Forty-four patients were randomly assigned to either study part A (n=26) or part B (n=18). In total, 3 patients withdrew before dosing, 27 received active treatment, and 14 received placebo. The majority of adverse events were mild. Two serious adverse events occurred, with one occurring after drug administration. In parts A and B, there was a dose-dependent increase in Tregs. In part B, the estimated dose to achieve a 75% increase in Tregs was 1.46 × 106 IU (95% confidence interval, 1.06 to 1.87). Single-cell RNA-sequencing demonstrated the engagement of distinct pathways and cellcell interactions. CONCLUSIONS: In this phase 1b/2a study, low-dose IL-2 expanded Tregs without adverse events of major concern. Larger trials are needed to confirm the safety and to further evaluate the efficacy of low-dose IL-2 as an anti-inflammatory therapy for patients with ischemic heart disease. (Funded by the Medical Research Council, the British Heart Foundation, and others; ClinicalTrials.gov number, NCT03113773)
Asunto(s)
Interleucina-2 , Interleucina-2/análogos & derivados , Isquemia Miocárdica , Linfocitos T Reguladores , Humanos , Interleucina-2/administración & dosificación , Interleucina-2/uso terapéutico , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Isquemia Miocárdica/inmunología , Isquemia Miocárdica/tratamiento farmacológico , Método Doble Ciego , Masculino , Persona de Mediana Edad , Femenino , Proteínas RecombinantesRESUMEN
High-dose interleukin-2 (HD IL-2) has curative potential in metastatic melanoma (MM) and renal cell carcinoma (RCC). Radiotherapy (RT) kills cancer cells and induces immunomodulatory effects. Prospective trials exploring clinical and immunological properties of combined RT/HD IL-2 are still needed. We designed a phase II, single-arm clinical trial for patients with MM and RCC. The treatment schedule consisted of 3 daily doses of 6-12 Gy of RT to 1-5 non-index metastatic fields, before IL-2 at the first and third treatment cycle. HD IL-2 was administered by continuous infusion for 72 hours and repeated every 3 weeks for up to 4 cycles, thereafter every 4 weeks for a maximum of 2 cycles. The primary endpoint was the immunological efficacy of the combined RT/HD IL-2 treatment (assessed by IFN-γ ELISPOT). Nineteen out of 22 patients were evaluable for immunological and clinical response. Partial response occurred in 3 (15.7%) patients and stable disease was observed in 7 (36.8%). The disease control rate was 52.6% after a median follow up of 39.2 months. According to Common Terminology Criteria for Adverse Events 4.0 (CTCAE 4.0), the majority of toxicities were grade 1-2. Immunological responses were frequent and detected in 16 (84.2%) patients. Increased levels of IL-8 and IL-10 in melanoma, circulating effector memory CD4+ and intratumoral CD8+ T cells in both tumor types were detected after therapy. Overall the treatment was well tolerated and immunologically active. Immunomonitoring and correlative data on tumor and peripheral blood cell subsets suggest that this combination treatment could be a promising strategy for patients progressing after standard treatments.
Asunto(s)
Antineoplásicos/administración & dosificación , Carcinoma de Células Renales/terapia , Quimioradioterapia , Interleucina-2/análogos & derivados , Neoplasias Renales/terapia , Melanoma/terapia , Neoplasias Cutáneas/terapia , Adulto , Anciano , Antineoplásicos/efectos adversos , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/secundario , Quimioradioterapia/efectos adversos , Fraccionamiento de la Dosis de Radiación , Femenino , Humanos , Infusiones Intravenosas , Interleucina-2/administración & dosificación , Interleucina-2/efectos adversos , Italia , Neoplasias Renales/inmunología , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Masculino , Melanoma/inmunología , Melanoma/metabolismo , Melanoma/secundario , Persona de Mediana Edad , Prueba de Estudio Conceptual , Estudios Prospectivos , Dosis de Radiación , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Factores de Tiempo , Resultado del TratamientoRESUMEN
Combination immunotherapy with sequential administration may enhance metastatic melanoma (MM) patients with long-term disease control. High Dose Aldesleukin/Recombinant Interleukin-2 (HD rIL-2) and ipilimumab (IPI) offer complementary mechanisms against MM. This phase IV study assessed the sequenced use of HD rIL-2 and IPI in MM patients. Eligible Stage IV MM patients were randomized to treatment with either two courses of HD rIL-2(600,000 IU/kg) followed by four doses of IPI 3 mg/kg or vice-versa. The primary objective was to compare one-year overall survival (OS) with historical control (46%, Hodi et al., NEJM 2010). Secondary objectives were 1-year progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) profile. Evaluable Population (EP) included patients who received at least 50% of planned treatment with each drug. Thirteen and 16 patients were randomized to receive HD rIL-2 first, and IPI first, respectively. One-year OS rate was 75% for intention to treat population. Eighteen patients were included in EP, 8 in HD rIL-2, 10 in IPI first arm. In EP, 1-year OS, PFS and ORR rates were 87%, 68%, and 50%, respectively. The frequency of AEs was similar in both arms with 13 patients experiencing Grade 3 or higher AEs, 3 resulting in the end of study participation. There was one HD rIL-2-related death, from cerebral hemorrhage due to thrombocytopenia. In this study with small sample size, HD rIL-2 and IPI were safe to administer sequentially in MM patients and showed more than additive effects. 1-year OS was superior to that of IPI alone from historical studies.
Asunto(s)
Interleucina-2 , Melanoma , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Humanos , Interleucina-2/análogos & derivados , Interleucina-2/uso terapéutico , Ipilimumab/efectos adversos , Melanoma/tratamiento farmacológico , Nivolumab/uso terapéutico , Proteínas RecombinantesRESUMEN
Adoptive transfer of antigen-specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in some patients1. Both the number of transferred T cells and their differentiation state are critical determinants of effective responses2,3. T cells can be expanded with T cell receptor (TCR)-mediated stimulation and interleukin-2, but this can lead to differentiation into effector T cells4,5 and lower therapeutic efficacy6, whereas maintenance of a more stem-cell-like state before adoptive transfer is beneficial7. Here we show that H9T, an engineered interleukin-2 partial agonist, promotes the expansion of CD8+ T cells without driving terminal differentiation. H9T led to altered STAT5 signalling and mediated distinctive downstream transcriptional, epigenetic and metabolic programs. In addition, H9T treatment sustained the expression of T cell transcription factor 1 (TCF-1) and promoted mitochondrial fitness, thereby facilitating the maintenance of a stem-cell-like state. Moreover, TCR-transgenic and chimeric antigen receptor-modified CD8+ T cells that were expanded with H9T showed robust anti-tumour activity in vivo in mouse models of melanoma and acute lymphoblastic leukaemia. Thus, engineering cytokine variants with distinctive properties is a promising strategy for creating new molecules with translational potential.
Asunto(s)
Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Agonismo Parcial de Drogas , Interleucina-2/análogos & derivados , Interleucina-2/agonistas , Proteínas Mutantes/farmacología , Células Madre/efectos de los fármacos , Animales , Linfocitos T CD8-positivos/inmunología , Interleucina-2/química , Interleucina-2/genética , Melanoma/metabolismo , Ratones , Mitocondrias/efectos de los fármacos , Proteínas Mutantes/química , Proteínas Mutantes/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Factor de Transcripción STAT5/metabolismo , Células Madre/citología , Factor 1 de Transcripción de Linfocitos T/metabolismo , Investigación Biomédica TraslacionalRESUMEN
PURPOSE: Therapies that produce deep and durable responses in patients with metastatic melanoma are needed. This phase II cohort from the international, single-arm PIVOT-02 study evaluated the CD122-preferential interleukin-2 pathway agonist bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in first-line metastatic melanoma. METHODS: A total of 41 previously untreated patients with stage III/IV melanoma received BEMPEG 0.006 mg/kg plus NIVO 360 mg once every 3 weeks for ≤ 2 years; 38 were efficacy-evaluable (≥ 1 postbaseline scan). Primary end points were safety and objective response rate (blinded independent central review); other end points included progression-free survival, overall survival (OS), and exploratory biomarkers. RESULTS: At 29.0 months' median follow-up, the objective response rate was 52.6% (20 of 38 patients), and the complete response rate was 34.2% (13 of 38 patients). Median change in size of target lesions from baseline was -78.5% (response-evaluable population); 47.4% (18 of 38 patients) experienced complete clearance of target lesions. Median progression-free survival was 30.9 months (95% CI, 5.3 to not estimable). Median OS was not reached; the 24-month OS rate was 77.0% (95% CI, 60.4 to 87.3). Grade 3 and 4 treatment-related and immune-mediated adverse events occurred in 17.1% (7 of 41) and 4.9% (2 of 41) of patients, respectively. Increased polyfunctional responses in CD8+ and CD4+ T cells were seen in blood after treatment, driven by cytokines with effector functions. Early on-treatment blood biomarkers (CD8+ polyfunctional strength difference and eosinophils) correlated with treatment response. CONCLUSION: BEMPEG in combination with NIVO was tolerated, with relatively low rates of grade 3 and 4 treatment-related and immune-mediated adverse events. The combination had encouraging antitumor activity in first-line metastatic melanoma, including an extended median progression-free survival. Exploratory analyses associated noninvasive, on-treatment biomarkers with response, before radiologic evidence was observed.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Interleucina-2/análogos & derivados , Melanoma/tratamiento farmacológico , Nivolumab/uso terapéutico , Polietilenglicoles/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Europa (Continente) , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Interleucina-2/efectos adversos , Interleucina-2/uso terapéutico , Masculino , Melanoma/mortalidad , Melanoma/secundario , Persona de Mediana Edad , Estadificación de Neoplasias , Nivolumab/efectos adversos , Polietilenglicoles/efectos adversos , Supervivencia sin Progresión , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Factores de Tiempo , Estados UnidosRESUMEN
BACKGROUND: Current clinical trials are using radiation therapy (RT) to enhance an antitumor response elicited by high-dose interleukin (IL)-2 therapy or immune checkpoint blockade (ICB). Bempegaldesleukin (BEMPEG) is an investigational CD122-preferential IL-2 pathway agonist with prolonged in vivo half-life and preferential intratumoral expansion of T effector cells over T regulatory cells. BEMPEG has shown encouraging safety and efficacy in clinical trials when used in combination with PD-1 checkpoint blockade. In this study, we investigated the antitumor effect of local RT combined with BEMPEG in multiple immunologically 'cold' tumor models. Additionally, we asked if ICB could further enhance the local and distant antitumor effect of RT+BEMPEG in the setting of advanced solid tumors or metastatic disease. METHODS: Mice bearing flank tumors (B78 melanoma, 4T1 breast cancer, or MOC2 head and neck squamous cell carcinoma) were treated with combinations of RT and immunotherapy (including BEMPEG, high-dose IL-2, anti(α)-CTLA-4, and α-PD-L1). Mice bearing B78 flank tumors were injected intravenously with B16 melanoma cells to mimic metastatic disease and were subsequently treated with RT and/or immunotherapy. Tumor growth and survival were monitored. Peripheral T cells and tumor-infiltrating lymphocytes were assessed via flow cytometry. RESULTS: A cooperative antitumor effect was observed in all models when RT was combined with BEMPEG, and RT increased IL-2 receptor expression on peripheral T cells. This cooperative interaction was associated with increased IL-2 receptor expression on peripheral T cells following RT. In the B78 melanoma model, RT+BEMPEG resulted in complete tumor regression in the majority of mice with a single ~400 mm3 tumor. This antitumor response was T-cell dependent and supported by long-lasting immune memory. Adding ICB to RT+BEMPEG strengthened the antitumor response and cured the majority of mice with a single ~1000 mm3 B78 tumor. In models with disseminated metastasis (B78 primary with B16 metastasis, 4T1, and MOC2), the triple combination of RT, BEMPEG, and ICB significantly improved primary tumor response and survival. CONCLUSION: The combination of local RT, BEMPEG, and ICB cured mice with advanced, immunologically cold tumors and distant metastasis in a T cell-dependent manner, suggesting this triple combination warrants clinical testing.
Asunto(s)
Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Interleucina-2/análogos & derivados , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Polietilenglicoles/uso terapéutico , Radioterapia/métodos , Animales , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Interleucina-2/farmacología , Interleucina-2/uso terapéutico , Ratones , Metástasis de la Neoplasia , Polietilenglicoles/farmacologíaRESUMEN
IL-2 is the master-regulator cytokine for T cell dependent responses and is crucial for proliferation and survival of T cells. However, IL-2-based treatments remained marginal, in part due to short half-life. Thus, we aimed to extend IL-2 half-life by flanking the IL-2 core with sequences derived from the extensively glycosylated hinge region of the NCR2 receptor. We termed this modified IL-2: "S2A". Importantly, S2A blood half-life was extended 14-fold compared to the clinical grade IL-2, Proleukin. Low doses inoculation of S2A significantly enhanced induction of Tregs (CD4+ Regulatory T cells) in vivo, as compared to Proleukin, while both S2A and Proleukin induced low levels of CD8+ T cells. In a B16 metastatic melanoma model, S2A treatment was unable to reduce the metastatic capacity of B16 melanoma, while enhancing induction and recruitment of Tregs, compared to Proleukin. Conversely, in two autoimmune models, rheumatoid arthritis and DSS-induced colitis, S2A treatment significantly reduced the progression of disease compared to Proleukin. Our results suggest new avenues for generating long-acting IL-2 for long-standing treatment and a new technique for manipulating short-life proteins for clinical and research uses.
Asunto(s)
Autoinmunidad/efectos de los fármacos , Interleucina-2/análogos & derivados , Receptor 2 Gatillante de la Citotoxidad Natural/química , Linfocitos T Reguladores/efectos de los fármacos , Animales , Artritis Reumatoide/prevención & control , Preparaciones de Acción Retardada , Evaluación Preclínica de Medicamentos , Glicosilación , Semivida , Interleucina-2/administración & dosificación , Interleucina-2/farmacocinética , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Survival of patients with relapsed/refractory osteosarcoma has not improved in the last 30 years. Several immunotherapeutic approaches have shown benefit in murine osteosarcoma models, including the anti-programmed death-1 (anti-PD-1) and anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) immune checkpoint inhibitors. Treatment with the T-cell growth factor interleukin-2 (IL-2) has shown some clinical benefit but has limitations due to poor tolerability. Therefore, we evaluated the efficacy of bempegaldesleukin (BEMPEG; NKTR-214), a first-in-class CD122-preferential IL-2 pathway agonist, alone and in combination with anti-PD-1 or anti-CTLA-4 immune checkpoint inhibitors in metastatic and orthotopic murine models of osteosarcoma. Treatment with BEMPEG delayed tumor growth and increased overall survival of mice with K7M2-WT osteosarcoma pulmonary metastases. BEMPEG also inhibited primary tumor growth and metastatic relapse in lungs and bone in the K7M3 orthotopic osteosarcoma mouse model. In addition, it enhanced therapeutic activity of anti-CTLA-4 and anti-PD-1 checkpoint blockade in the DLM8 subcutaneous murine osteosarcoma model. Finally, BEMPEG strongly increased accumulation of intratumoral effector T cells and natural killer cells, but not T-regulatory cells, resulting in improved effector:inhibitory cell ratios. Collectively, these data in multiple murine models of osteosarcoma provide a path toward clinical evaluation of BEMPEG-based regimens in human osteosarcoma.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Óseas/tratamiento farmacológico , Modelos Animales de Enfermedad , Interleucina-2/análogos & derivados , Osteosarcoma/tratamiento farmacológico , Polietilenglicoles/farmacología , Animales , Neoplasias Óseas/inmunología , Neoplasias Óseas/patología , Línea Celular Tumoral , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Interleucina-2/administración & dosificación , Interleucina-2/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/secundario , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Osteosarcoma/inmunología , Osteosarcoma/patología , Polietilenglicoles/administración & dosificación , Análisis de Supervivencia , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/patología , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacos , Carga Tumoral/inmunologíaRESUMEN
The choice of first-line therapy for patients with metastatic urothelial cancer (mUC) is based on cisplatin-eligibility and programmed death-ligand 1 (PD-L1) status. For patients with mUC who are ineligible for cisplatin and with low PD-L1 expression, chemotherapy-based regimens are the only approved first-line option. In a Phase I/II trial of the chemotherapy-free regimen, bempegaldesleukin (BEMPEG; NKTR-214) plus nivolumab, patients with locally advanced or mUC experienced tumor responses regardless of baseline PD-L1 expression (objective response rates: 50 and 45% in patients with PD-L1-positive and -negative tumors, respectively). The Phase II PIVOT-10 study (NCT03785925), evaluates efficacy and safety of first-line BEMPEG plus nivolumab in cisplatin-ineligible patients with locally advanced or mUC. Most patients will have low PD-L1 expression. Primary end point: objective response rates (including complete response).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proyectos de Investigación , Neoplasias Urológicas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor , Cisplatino/administración & dosificación , Humanos , Interleucina-2/administración & dosificación , Interleucina-2/análogos & derivados , Terapia Molecular Dirigida , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , Nivolumab/administración & dosificación , Polietilenglicoles/administración & dosificación , Pronóstico , Neoplasias Urológicas/diagnóstico , Neoplasias Urológicas/etiología , Neoplasias Urológicas/mortalidadRESUMEN
Advancements in science enable researchers to constantly innovate and create novel biologics. However, the use of non-human animal models during the development of biologics impedes identification of precise in vivo interactions between the human immune system and treatments. Due to lack of this understanding, adverse effects are frequently observed in healthy volunteers and patients exposed to potential biologics during clinical trials. In this study, we evaluated and compared the effects of known immunotoxic biologics, Proleukin®/IL-2 and OKT3 in humanized mice (reconstituted with human fetal cells) to published clinical outcomes. We demonstrated that humanized mice were able to recapitulate in vivo pathological changes and human-specific immune responses, such as elevated cytokine levels and modulated lymphocytes and myeloid subsets. Given the high similarities of immunological side effects observed between humanized mice and clinical studies, this model could be used to assess immunotoxicity of biologics at a pre-clinical stage, without placing research participants and/or patients at risk.
Asunto(s)
Interleucina-2/análogos & derivados , Modelos Inmunológicos , Animales , Evaluación de Medicamentos , Feto , Humanos , Interleucina-2/efectos adversos , Interleucina-2/inmunología , Interleucina-2/farmacología , Ratones , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/farmacologíaRESUMEN
In this issue of Cancer Discovery, Diab and colleagues demonstrate in a phase I trial enrolling 38 patients diagnosed with advanced solid tumors that combining the pegylated IL2 bempegaldesleukin with an anti-PD-1 mAb is safe, with an overall response rate of 59.5%. This compelling clinical activity is supported by the potent immune proliferation and activation of circulating T and natural killer cells with a >4-fold increase in the CD8/regulatory T-cell ratio in tumors, independent of baseline PD-L1 expression.See related article by Diab et al., p. 1158.
Asunto(s)
Interleucina-2 , Neoplasias , Anticuerpos Monoclonales , Antígeno B7-H1 , Linfocitos T CD8-positivos , Humanos , Interleucina-2/análogos & derivados , Neoplasias/tratamiento farmacológico , Nivolumab , Néctar de las Plantas , PolietilenglicolesRESUMEN
BACKGROUND: Low-dose interleukin-2 (ld-IL-2) enhances regulatory T-cell (Treg) function in auto-inflammatory conditions. Neuroinflammation being a pathogenic feature of amyotrophic lateral sclerosis (ALS), we evaluated the pharmacodynamics and safety of ld-IL-2 in ALS subjects. METHODS: We performed a single centre, parallel three-arm, randomised, double-blind, placebo-controlled study. Eligibility criteria included age < 75 years, disease duration < 5 years, riluzole treatment > 3 months, and a slow vital capacity ≥ 70% of normal. Patients were randomised (1:1:1) to aldesleukin 2 MIU, 1 MIU, or placebo once daily for 5 days every 4 weeks for 3 cycles. Primary outcome was change from baseline in Treg percentage of CD4+ T cells (%Tregs) following a first cycle. Secondary laboratory outcomes included: %Treg and Treg number following repeated cycles, and plasma CCL2 and neurofilament light chain protein (NFL) concentrations as surrogate markers of efficacy. Safety outcomes included motor-function (ALSFRS-R), slow vital capacity (SVC), and adverse event reports. This trial is registered with ClinicalTrials.gov, NCT02059759. FINDINGS: All randomised patients (12 per group), recruited from October 2015 to December 2015, were alive at the end of follow-up and included in the intent-to-treat (ITT) analysis. No drug-related serious adverse event was observed. Non-serious adverse events occurred more frequently with the 1 and 2 MIU IL-2 doses compared to placebo, including injection site reactions and flu-like symptoms. Primary outcome analysis showed a significant increase (p < 0·0001) in %Tregs in the 2 MIU and 1 MIU arms (mean [SD]: 2 MIU: +6·2% [2·2]; 1 MIU: +3·9% [1·2]) as compared to placebo (mean [SD]: -0·49% [1·3]). Effect sizes (ES) were large in treated groups: 2 MIU ES=3·7 (IC95%: 2·3-4·9) and 1 MIU ES=3·5 (IC95%: 2·1-4·6). Secondary outcomes showed a significant increase in %Tregs following repeated cycles (p < 0·0001) as compared to placebo, and a dose-dependent decrease in plasma CCL2 (p = 0·0049). There were no significant differences amongst the three groups on plasma NFL levels. INTERPRETATION: Ld-IL-2 is well tolerated and immunologically effective in subjects with ALS. These results warrant further investigation into their eventual therapeutic impact on slowing ALS disease progression. FUNDING: The French Health Ministry (PHRC-I-14-056), EU H2020 (grant #633413), and the Association pour la Recherche sur la SLA (ARSLA).
Asunto(s)
Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Interleucina-2/análogos & derivados , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/etiología , Esclerosis Amiotrófica Lateral/metabolismo , Biomarcadores , Quimiocinas , Citocinas , Femenino , Humanos , Inmunofenotipificación , Interleucina-2/administración & dosificación , Interleucina-2/metabolismo , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/administración & dosificación , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Resultado del TratamientoRESUMEN
Mucin-type O-glycosylation (hereafter referred to as O-GalNAc glycosylation) is one of the most abundant glycosylation on proteins. It is initiated by the members of polypeptide N-acetyl-α-galactosaminyltransferases (ppGalNAc-Ts) family. The ppGalNAc-Ts could be used as tool enzymes to modify target proteins including therapeutic glycoprotein drugs with O-GalNAc glycosylation at specific glycosylated sites in vitro. Obtaining a large amount of ppGalNAc-T can greatly increase the yield of therapeutic O-glycoprotein and reduce the culture costs. In this study, we reported a simple Escherichia coli (E. coli) expression system capable of producing human ppGalNAc-Ts. By co-expressing human PDI, we could simply obtain active ppGalNAc-Ts with high efficiency. Using the E. coli expressed ppGalNAc-T2, we site-specifically synthesized O-glycosylated IL-2 at the native glycosylated site Thr23 residue. These results reveal the E. coli system we constructed is suitable to produce active ppGalNAc-Ts and thus has the potential value for basic research and production of therapeutic O-glycoproteins in vitro.
Asunto(s)
Interleucina-2/análogos & derivados , N-Acetilgalactosaminiltransferasas/genética , N-Acetilgalactosaminiltransferasas/metabolismo , Secuencia de Aminoácidos , Biocatálisis , Dominio Catalítico/genética , Disulfuros/química , Escherichia coli/genética , Escherichia coli/metabolismo , Expresión Génica , Glicosilación , Humanos , Interleucina-2/biosíntesis , Interleucina-2/química , Modelos Moleculares , N-Acetilgalactosaminiltransferasas/química , Plásmidos/genética , Dominios Proteicos , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Polipéptido N-AcetilgalactosaminiltransferasaRESUMEN
This single-arm, phase I dose-escalation trial (NCT02983045) evaluated bempegaldesleukin (NKTR-214/BEMPEG), a CD122-preferential IL2 pathway agonist, plus nivolumab in 38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, renal cell carcinoma, and non-small cell lung cancer). Three dose-limiting toxicities were reported in 2 of 17 patients during dose escalation [hypotension (n = 1), hyperglycemia (n = 1), metabolic acidosis (n = 1)]. The most common treatment-related adverse events (TRAE) were flu-like symptoms (86.8%), rash (78.9%), fatigue (73.7%), and pruritus (52.6%). Eight patients (21.1%) experienced grade 3/4 TRAEs; there were no treatment-related deaths. Total objective response rate across tumor types and dose cohorts was 59.5% (22/37), with 7 complete responses (18.9%). Cellular and gene expression analysis of longitudinal tumor biopsies revealed increased infiltration, activation, and cytotoxicity of CD8+ T cells, without regulatory T-cell enhancement. At the recommended phase II dose, BEMPEG 0.006 mg/kg plus nivolumab 360 mg every 3 weeks, the combination was well tolerated and demonstrated encouraging clinical activity irrespective of baseline PD-L1 status. SIGNIFICANCE: These data show that BEMPEG can be successfully combined with a checkpoint inhibitor as dual immunotherapy for a range of advanced solid tumors. Efficacy was observed regardless of baseline PD-L1 status and baseline levels of tumor-infiltrating lymphocytes, suggesting therapeutic potential for patients with poor prognostic risk factors for response to PD-1/PD-L1 blockade.See related commentary by Rouanne et al., p. 1097.This article is highlighted in the In This Issue feature, p. 1079.
Asunto(s)
Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Renales/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Interleucina-2/análogos & derivados , Neoplasias Renales/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Nivolumab/administración & dosificación , Polietilenglicoles/administración & dosificación , Adulto , Anciano , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/inmunología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunoterapia , Interleucina-2/administración & dosificación , Interleucina-2/efectos adversos , Neoplasias Renales/genética , Neoplasias Renales/inmunología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Recuento de Linfocitos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Melanoma/genética , Melanoma/inmunología , Persona de Mediana Edad , Nivolumab/efectos adversos , Polietilenglicoles/efectos adversos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: High-dose radiotherapy (RT) is known to be immunogenic, but is rarely capable of driving clinically relevant abscopal antitumor immunity as monotherapy. RT is known to increase antigen presentation, type I/II interferon responses, and immune cell trafficking to irradiated tumors. Bempegaldesleukin (NKTR-214) is a CD122-preferential interleukin 2 (IL-2) pathway agonist that has been shown to increase tumor-infiltrating lymphocytes, T cell clonality, and increase PD-1 expression. NKTR-214 has increased drug half-life, decreased toxicity, and increased CD8+ T cell and natural killer cell stimulation compared with IL-2. METHODS: Animals bearing bilateral subcutaneous MCA-205 fibrosarcoma or CT26 colorectal tumors were treated with NKTR-214, RT, or combination therapy, and tumor growth of irradiated and abscopal lesions was assessed. Focal RT was delivered using a small animal radiation research platform. Peripheral and tumor-infiltrating immune phenotype and functional analyses were performed by flow cytometry. RNA expression profiling from both irradiated and abscopal lesions was performed using microarray. RESULTS: We demonstrate synergy between RT of a single tumor and NKTR-214 systemic therapy resulting in dramatically increased cure rates of mice bearing bilateral tumors compared with RT or NKTR-214 therapy alone. Combination therapy resulted in increased magnitude and effector function of tumor-specific CD8+ T cell responses and increased trafficking of these T cells to both irradiated and distant, unirradiated, tumors. CONCLUSIONS: Given the increasing role of hypofractionated and stereotactic body RT as standard of care treatments in the management of locally advanced and metastatic cancer, these data have important implications for future clinical trial development. The combination of RT and NKTR-214 therapy potently stimulates systemic antitumor immunity and should be evaluated for the treatment of patients with locally advanced and metastatic solid tumors.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Neoplasias Colorrectales/terapia , Fibrosarcoma/terapia , Interleucina-2/análogos & derivados , Linfocitos Infiltrantes de Tumor/inmunología , Polietilenglicoles/uso terapéutico , Radioterapia/métodos , Sarcoma Experimental/terapia , Animales , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Terapia Combinada , Femenino , Fibrosarcoma/inmunología , Fibrosarcoma/patología , Inmunoterapia/métodos , Interleucina-2/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Sarcoma Experimental/inmunología , Sarcoma Experimental/patología , Linfocitos T Reguladores/inmunologíaRESUMEN
Mechanism-based strategies to overcome resistance to PD-1 blockade therapy are urgently needed. We developed genetic acquired resistant models of JAK1, JAK2, and B2M loss-of-function mutations by gene knockout in human and murine cell lines. Human melanoma cell lines with JAK1/2 knockout became insensitive to IFN-induced antitumor effects, while B2M knockout was no longer recognized by antigen-specific T cells and hence was resistant to cytotoxicity. All of these mutations led to resistance to anti-PD-1 therapy in vivo. JAK1/2-knockout resistance could be overcome with the activation of innate and adaptive immunity by intratumoral Toll-like receptor 9 agonist administration together with anti-PD-1, mediated by natural killer (NK) and CD8 T cells. B2M-knockout resistance could be overcome by NK-cell and CD4 T-cell activation using the CD122 preferential IL2 agonist bempegaldesleukin. Therefore, mechanistically designed combination therapies can overcome genetic resistance to PD-1 blockade therapy. SIGNIFICANCE: The activation of IFN signaling through pattern recognition receptors and the stimulation of NK cells overcome genetic mechanisms of resistance to PD-1 blockade therapy mediated through deficient IFN receptor and antigen presentation pathways. These approaches are being tested in the clinic to improve the antitumor activity of PD-1 blockade therapy.This article is highlighted in the In This Issue feature, p. 1079.
Asunto(s)
Resistencia a Antineoplásicos/genética , Janus Quinasa 1/genética , Janus Quinasa 2/genética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Microglobulina beta-2/genética , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Interferones/farmacología , Interleucina-2/análogos & derivados , Interleucina-2/inmunología , Interleucina-2/farmacología , Interleucina-2/uso terapéutico , Células Asesinas Naturales/inmunología , Mutación con Pérdida de Función , Ratones Endogámicos C57BL , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/inmunología , Polietilenglicoles/farmacología , Polietilenglicoles/uso terapéutico , Receptor Toll-Like 9/inmunologíaRESUMEN
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.
Asunto(s)
Traslado Adoptivo , Interleucina-2/análogos & derivados , Interleucina-2/agonistas , Melanoma/tratamiento farmacológico , Polietilenglicoles/administración & dosificación , Receptores de Interleucina-2/inmunología , Linfocitos T/inmunología , Animales , Humanos , Interleucina-2/administración & dosificación , Interleucina-2/inmunología , Activación de Linfocitos/efectos de los fármacos , Melanoma/genética , Melanoma/inmunología , Melanoma Experimental , Ratones , Ratones Endogámicos C57BL , Receptores de Interleucina-2/genéticaRESUMEN
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.