135 research outputs found
Recombinant interleukin-21 plus sorafenib for metastatic renal cell carcinoma: a phase 1/2 study
Abstract
Background
Despite the positive impact of targeted therapies on metastatic renal cell carcinoma (mRCC), durable responses are infrequent and an unmet need exists for novel therapies with distinct mechanisms of action. We investigated the combination of recombinant Interleukin 21 (IL-21), a cytokine with unique immunostimulatory properties, plus sorafenib, a VEGFR tyrosine kinase inhibitor.
Methods
In this phase 1/2 study, 52 mRCC patients received outpatient treatment with oral sorafenib 400 mg twice daily plus intravenous IL-21 (10–50 mcg/kg) on days 1–5 and 15–19 of each 7-week treatment course. The safety, antitumor activity, pharmacokinetic and pharmacodynamic effects of the combination were evaluated.
Results
In phase 1 (n = 19), the maximum tolerated dose for IL-21 with the standard dose of sorafenib was determined to be 30 mcg/kg/day; grade 3 skin rash was the only dose-limiting toxicity. In phase 2, 33 previously-treated patients tolerated the combination therapy well with appropriate dose reductions; toxicities were mostly grade 1 or 2. The objective response rate was 21% and disease control rate was 82%. Two patients have durable responses that are ongoing, despite cessation of both IL-21 and sorafenib, at 41+ and 30+ months, respectively. The median progression-free survival in phase 2 was 5.6 months. The pharmacokinetic and pharmacodynamic properties of IL-21 appeared to be preserved in the presence of sorafenib.
Conclusion
IL-21 plus sorafenib has antitumor activity and acceptable safety in previously treated mRCC patients. IL-21 may represent a suitable immunotherapy in further exploration of combination strategies in mRCC.
Trial registration
ClinicalTrials.gov Identifier: NCT0038928
Regulatory T-Cells and Associated Pathways in Metastatic Renal Cell Carcinoma (mRCC) Patients Undergoing DC-Vaccination and Cytokine-Therapy
Purpose: To evaluate CD4+CD25+FOXP3+ T regulatory cells (TREG) and associated immune-regulatory pathways in peripheral blood lymphocytes (PBL) of metastatic renal cell carcinoma (mRCC) patients and healthy volunteers. We subsequently investigated the effects of immunotherapy on circulating TREG combining an extensive phenotype examination, DNA methylation analysis and global transcriptome analysis.
Design: Eighteen patients with mRCC and twelve volunteers (controls) were available for analysis. TREG phenotype was examined using flow cytometry (FCM). TREG were also quantified by analyzing the epigenetic status of the FOXP3 locus using methylation specific PCR. As a third approach, RNA of the PBL was hybridized to Affymetrix GeneChip Human Gene 1.0 ST Arrays and the gene signatures were explored using pathway analysis. Results We observed higher numbers of TREG in pre-treatment PBL of mRCC patients compared to controls. A significant increase in TREG was detected in all mRCC patients after the two cycles of immunotherapy. The expansion of TREG was significantly higher in non-responders than in responding patients. Methylation specific PCR confirmed the FCM data and circumvented the variability and subjectivity of the FCM method. Gene Set Enrichment Analysis (GSEA) of the microarray data showed significant enrichment of FOXP3 target genes, CTLA-4 and TGF-ß associated pathways in the patient cohort.
Conclusion: Immune monitoring of the peripheral blood and tumor tissue is important for a wide range of diseases and treatment strategies. Adoption of methodology for quantifying TREG with the least variability and subjectivity will enhance the ability to compare and interpret findings across studies
Role of Interferons in the Thearpy of Melanoma
A range of potent immunoregulatory molecules termed cytokines has become available for the therapy of human melanoma. Among the cytokines, the interferons (IFN) have been examined in great depth for the therapy of melanoma. IFN are able to modulate host effector cell function, including the tumor cytolytic function of lymphocytes and monocytes. IFN also have the capacity to regulate the distribution of circulating immunoregulatory (T) lymphocytes and the expression of tumor cell surface antigens, as well as class I and II products of the major histocompatibility locus. These activities of the IFN have led to their early application for treatment of human melanoma. The empirical evidence that IFN alpha exerts clinically significant anti-tumor effects against melanoma is reviewed, and evolving status of adjuvant trials of IFN alpha and gamma is noted. New indirect host-mediated anti-tumor activities that may potentially be manifest by IFN have yet to be fully harnessed. The opportunity to obtain meaningful anti-tumor activity in advanced disease or adjuvant settings, at dose ranges below those which are toxic (conventional maximal tolerable), are at hand. The U.S. cooperative groups [Eastern Cooperative Oncology Group (ECOG), Cancer and Leukemia Group B (CALGB), and South West Oncology Group (SWOG)] are studying IFN gamma in pursuit of this goal in advanced and adjuvant settings for melanoma and other tumors. The determination of the clinical role of IFN as biologic response modifiers demands equal commitment to the clinical assessment of immunobiologic mechanisms and anti-tumor effects. The immunologic assessment of IFN and a number of other cytokines cytokines such as interleukin-2 (IL-2) may be the most appropriate and is a major focus of the Pittsburgh Cancer Institute.Regional delivery of least toxic approach, given their half-life. Regional therapy by the intralesional route has yielded enhanced activity for a range of biologics, including bacillus Calmette-Guerin (BCG), IL-2, and tumor necrosis factor (TNF). Intralymphatic therapy with methanol extraction residue of BCG (MER-BCG) has been tested, and trials are now in progress with IL-2 to assess the optimal dosage by this route.It is likely that the optimal role of IFN and other cytokines will be found in combination with one another, and with different biologic modalities such as monoclonal antibodies and vaccines, to allow expansion and heightened activity of the desired effector cell populations in the host. Enhanced host toxicities, as well as anti-tumor effects, may require that special attention be devoted to optimal sequence of administration to enhance the therapeutic index
Cardiac Toxicity Associated with Immune Checkpoint Inhibitors: Case Series and Review of the Literature
The development of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of patients with advanced stage cancers. However, immune-related adverse events are frequently observed. Cardiac toxicity from ICI therapy can range from asymptomatic troponin-I elevations to conduction abnormalities of the heart and even fulminant myocarditis. Although rare, myocarditis is a potentially fatal adverse effect of ICI therapy. We present a series of five cases of ICI-related cardio-toxicity diagnosed and managed at Roswell Park Comprehensive Cancer Center along with a review of published case reports in the literature. Our series highlights the importance of high clinical suspicion, early diagnosis of myocarditis, and prompt initiation of immunosuppressive therapy
Recommended from our members
Validation of Melanoma Immune Profile (MIP), a Prognostic Immune Gene Prediction Score for Stage II–III Melanoma
Purpose: Biomarkers are needed to stratify patients with stage II–III melanoma for clinical trials of adjuvant therapy because, while immunotherapy is protective, it also confers the risk of severe toxicity. We previously defined and validated a 53-immune gene melanoma immune profile (MIP) predictive both of distant metastatic recurrence and of disease-specific survival (DSS). Here, we test MIP on a third independent population.
Experimental Design: A retrospective cohort of 78 patients with stage II–III primary melanoma was analyzed using the NanoString assay to measure expression of 53 target genes, and MIP score was calculated. Statistical analysis correlating MIP with DSS, overall survival, distant metastatic recurrence, and distant metastasis-free interval was performed using ROC curves, Kaplan–Meier curves, and standard univariable and multivariable Cox proportional hazards models.
Results: MIP significantly distinguished patients with distant metastatic recurrence from those without distant metastatic recurrence using ROC curve analysis (AUC = 0.695; P = 0.008). We defined high- and low-risk groups based on the cutoff defined by this ROC curve and find that MIP correlates with both DSS and overall survival by ROC curve analysis (AUC = 0.719; P = 0.004 and AUC = 0.698; P = 0.004, respectively). Univariable Cox regression reveals that a high-risk MIP score correlates with DSS (P = 0.015; HR = 3.2).
Conclusions: MIP identifies patients with low risk of death from melanoma and may constitute a clinical tool to stratify patients with stage II–III melanoma for enrollment in clinical trials
Recommended from our members
Perspectives in melanoma: meeting report from the Melanoma Bridge (December 5th-7th, 2019, Naples, Italy).
The melanoma treatment landscape changed in 2011 with the approval of the first anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 checkpoint inhibitor and of the first BRAF-targeted monoclonal antibody, both of which significantly improved overall survival (OS). Since then, improved understanding of the tumor microenvironment (TME) and tumor immune-evasion mechanisms has resulted in new approaches to targeting and harnessing the host immune response. The approval of new immune and targeted therapies has further improved outcomes for patients with advanced melanoma and other combination modalities are also being explored such as chemotherapy, radiotherapy, electrochemotherapy and surgery. In addition, different strategies of drugs administration including sequential or combination treatment are being tested. Approaches to overcome resistance and to potentiate the immune response are being developed. Increasing evidence emerges that tissue and blood-based biomarkers can predict the response to a therapy. The latest findings in melanoma research, including insights into the tumor microenvironment and new biomarkers, improved understanding of tumor immune response and resistance, novel approaches for combination strategies and the role of neoadjuvant and adjuvant therapy, were the focus of discussions at the Melanoma Bridge meeting (5-7 December, 2019, Naples, Italy), which are summarized in this report
Regulatory T-Cells and Associated Pathways in Metastatic Renal Cell Carcinoma (mRCC) Patients Undergoing DC-Vaccination and Cytokine-Therapy
To evaluate CD4(+)CD25(+)FOXP3(+) T regulatory cells (T(REG)) and associated immune-regulatory pathways in peripheral blood lymphocytes (PBL) of metastatic renal cell carcinoma (mRCC) patients and healthy volunteers. We subsequently investigated the effects of immunotherapy on circulating T(REG) combining an extensive phenotype examination, DNA methylation analysis and global transcriptome analysis
A multi-center study of high dose Aldesleukin (Proleukin® (HD IL-2) + Vemurafenib Zelboraf® ) therapy in patients with BRAFV600 mutation positive metastatic melanoma (proclivity 01)
Purpose: To investigate whether the Vemurafenib-induced increased tumor antigen expression, T lymphocyte infiltration and tumor debulking improve the complete response rate induced by HD IL-2 in metastatic melanoma and if there is synergistic toxicity using the drugs in close approximation. Schema: Adult patients with measurable metastatic or unresectable Stage III melanoma with no prior therapy and a BRAFV600 mutation who are candidates for HD IL-2 are eligible for entry into the first cohort of 135 patients (figure 1). Six weeks of Vemurafenib therapy per package insert precedes up to 2 courses of HD IL-2. Vemurafenib is administered during the outpatient intervals between cycles of HD IL-2 and following completion. A second cohort of up to 50 similar patients already responding or stable with < 18 weeks of Vemurafenib therapy will also be accrued. The study was amended to permit prior anti-PD-1 therapy. The primary endpoint is Complete Response (CR) and near CR at 6 months of therapy. Current status: Sixteen sites have enrolled patients. 41 patients have been enrolled to date, 27 in Cohort 1 and 14 in cohort 2. The Data Safety and Monitoring Board performed an initial safety analysis after the initial 8 patients which demonstrated no unexpected safety signal. An analysis of the effect of the combination on Progression Free Survival in both cohorts will be performed after the first 20% of patients in Cohort 1 have received at least one course of HD IL-2. The results of this analysis should be available at the time of the SITC meeting. Figure 1 Treatment of metastatic melanoma with HD IL-2 immunotherapy and targeted agent vemurafenib Treatment of metastatic melanoma with HD IL-2 immunotherapy and targeted agent vemurafenib
Gene expression profile of peripheral blood lymphocytes from renal cell carcinoma patients treated with IL-2, Interferon-α and dendritic cell vaccine
© The Author(s), 2012. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS One 7 (2012): e50221, doi:10.1371/journal.pone.0050221.Lymphocytes are a key component of the immune system and their differentiation and function are directly influenced by cancer. We examined peripheral blood lymphocyte (PBL) gene expression as a biomarker of illness and treatment effect using the Affymetrix Human Gene ST1 platform in patients with metastatic renal cell carcinoma (mRCC) who received combined treatment with IL-2, interferon-?-2a and dendritic cell vaccine. We examined gene expression, cytokine levels in patient serum and lymphocyte subsets as determined by flow cytometry (FCM). Pre-treatment PBLs from patients with mRCC exhibit a gene expression profile and serum cytokine profile consistent with inflammation and proliferation not found in healthy donors (HD). PBL gene expression from patients with mRCC showed increased mRNA of genes involved with T-cell and TREG-cell activation pathways, which was also reflected in lymphocyte subset distribution. Overall, PBL gene expression post-treatment (POST) was not significantly different than pre-treatment (PRE). Nevertheless, treatment related changes in gene expression (post-treatment minus pre-treatment) revealed an increased expression of T-cell and B-cell receptor signaling pathways in responding (R) patients compared to non-responding (NR) patients. In addition, we observed down-regulation of TREG-cell pathways post-treatment in R vs. NR patients. While exploratory in nature, this study supports the hypothesis that enhanced inflammatory cytotoxic pathways coupled with blunting of the regulatory pathways is necessary for effective anti-cancer activity associated with immune therapy. This type of analysis can potentially identify additional immune therapeutic targets in patients with mRCC.This work was supported by grants from the National Institutes of Health (RO1 CA5648, R21CA112761, P20RR016437, and P30CA023108)
- …