High-dose interleukin-2 (HD IL-2) in the treatment of advanced melanoma: The University of Pittsburgh experience.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9075-9075
Author(s):  
Diwakar Davar ◽  
Melissa Saul ◽  
Ahmad A. Tarhini ◽  
An Tran ◽  
Kerry Trent ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Interleukin 2 ◽  
Complete Response ◽  
Median Number ◽  
Cox Proportional Hazards ◽  
Advanced Melanoma ◽  
High Dose ◽  
Severe Toxicity ◽  
University Of Pittsburgh ◽  
Radiological Data

9075 Background: IL-2 is a T-cell growth factor tested in a variety of regimens for advanced melanoma (MEL) and renal cell carcinoma (RCC). High-dose IL-2 (600,000-720,000 IU/kg administered intravenously every 8 hours for up to 14 consecutive doses) was approved by FDA for advanced MEL and RCC in 1998 based upon the durability of responses observed. Early studies of HD IL-2 reported overall (OR) and complete response (CR) rates of 16% and 8% respectively. Severe toxicity limited use to specialized centers with standardized protocols, either intensive care (ICU) or oncology specialty settings. The U Pittsburgh has treated 1022 patients with IL-2 at any dosage and we here present outcomes of 550 MEL pts treated with HD IL-2 in an oncology specialty non-ICU setting. Methods: Clinical and radiological data were collected on all pts treated with IL-2 using the UPCI Cancer Registry and Medical Archival System (MARS). Pharmacy records were reviewed for dosing details. The influence of baseline characteristics on treatment outcomes was assessed using Cox proportional hazards analysis. Results: A total of 848 pts received HD IL-2, of which 298 pts had RCC while 550 had MEL. Detailed pharmacy dosing records were reviewed from 176 pts treated over the past 12 years (2000-2012) who received a total of 3738 cycles. Of 165 pts evaluable for response, OR was documented in 24 pts (14.8%) and CR in 5 pts (3.0%). Median overall survival (OS) was 10.0 mos for all patients and 21.5 mos for responders (CR+PR). Median number of doses per cycle was 7. Toxicity was consistent with prior reports. HD IL-2 required ICU transfers in 5% and 1 death was attributed to HD IL-2. Pts with higher baseline lactate dehydrogenase (LDH) had poorer OS (p < 0.05). Conclusions: In this large and uniformly treated series of recent patients treated with IL-2 OR/CR rates with HD IL-2 are 14.8% and 3.0% respectively. Higher LDH is associated with poorer outcome. Biomarkers of response are currently being evaluated in banked clinical specimens collected from patients under the SPORE in Skin Cancer (P50 CA121973).

Metastatic malignant melanoma treated with combined bolus and continuous infusion interleukin-2 and lymphokine-activated killer cells.

1990 ◽  
Vol 8 (7) ◽  
pp. 1138-1147 ◽  
Author(s):  
M H Bar ◽  
M Sznol ◽  
M B Atkins ◽  
N Ciobanu ◽  
K C Micetich ◽  
...  
Keyword(s):  
Lymph Node ◽  
Continuous Infusion ◽  
Lung Metastases ◽  
Interleukin 2 ◽  
Advanced Melanoma ◽  
Lak Cells ◽  
High Dose ◽  
Severe Toxicity ◽  
Lymphokine Activated Killer Cells

Fifty patients with advanced melanoma received high-dose bolus and continuous infusion interleukin-2 (IL-2) with lymphokine-activated killer (LAK) cells in an attempt to improve the therapeutic index of this active but toxic therapy. Treatment began with up to nine bolus doses of IL-2 administered over 3 days. After 1 day of rest, patients underwent daily leukapheresis for 4 days, and the leukocytes were cultured with IL-2 in vitro to prepare LAK cells. Continuous infusion IL-2 was begun 1 day after the last leukapheresis and continued for up to 148 hours; LAK cells were administered on days 1, 2, and 4 of the infusion. Responding patients were eligible to receive up to two additional cycles of therapy at 3-month intervals. Most patients completed each cycle without dose reduction. One patient had a complete response and six patients had partial responses (14% response rate). The complete responder and three of the partial responders (8%) remain free from disease progression with follow-up of 21 to 24 months. Of these four patients with durable remissions, one had extensive liver and lymph node metastases, one had lymph node, pleural, and parenchymal lung metastases, and two had disease limited to lymph nodes or subcutaneous tissues. Seventeen patients (34%) required pressors for hypotension, three patients (6%) developed hemodynamically significant arrhythmias, and six patients (12%) developed dyspnea at rest, but none required intubation and there were no treatment-related deaths. Unacceptable toxicity developed in two patients during bolus IL-2 administration and therapy was aborted; both returned to baseline status within 4 days of discontinuing IL-2. Fever, oliguria, and elevated creatinine or transaminase levels occurred frequently but were also transient. Despite less frequent severe toxicity with this modified regimen, these results confirm the ability of IL-2 and LAK cell therapy to induce durable remissions in some patients with advanced melanoma.

Association between rigors and overall survival (OS) in metastatic renal cell carcinoma (mRCC) patients treated with high-dose interleukin-2 (HD IL-2).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 487-487
Author(s):  
Julia Anne Batten ◽  
Wolfram E. Samlowski ◽  
Kinjal Parikh ◽  
Arun Sendilnathan ◽  
Hilda Crispin ◽  
...  
Keyword(s):  
Overall Survival ◽  
Proportional Hazards ◽  
Objective Response ◽  
Interleukin 2 ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
High Dose ◽  
University Of Utah ◽  
Cox Proportional Hazards Models ◽  
Grade 3

487 Background: HD IL-2 is associated with an objective response rate of 16-20% with durability of response in select mRCC patients. HD IL-2 is also associated with significant toxicity including vascular leak syndrome and inflammatory side effects. Few predictive markers can identify patients likely to respond to HD IL-2. Methods: Patients treated with HD IL-2 at the University of Utah Huntsman Cancer Institute from 2000 to 2012 with clear cell mRCC were evaluated. Grade of toxicities during HD IL-2 treatment were collected based on provider documentation in the electronic health record. Rates of adverse events (AEs) and overall survival stratified grade 3 AEs were evaluated by Kaplan-Meier survival estimates and Cox proportional hazards models. All AEs were graded per common terminology criteria version 4. Grade 3 rigors were defined as severe rigors requiring opioids. Results: A total of 85 patients were included with a median age of 56 years (range 32-76 years) and 79% (n = 67) were male. Patients belonged to the following MSKCC risk categories: 11 (13%) good, 70 (82%) intermediate, and 4 (5%) poor risk. The mean total dose received was 1097 MIU (range: 160 – 3048 MIU). The prevalence of grade 3 AEs is presented in the table. Median survival of patients with ≥grade 3 rigors after HD IL-2 administration was 1501 days vs 533 days for those without (p = 0.0005, HR 2.54). Presence of rigors was also associated with a significant improvement in progression free survival, time to next treatment and response rates. No other AEs predicted response to HD IL-2. Conclusions: Presence of grade 3 rigors predicts improved survival during HD IL-2 therapy. Notably, grade 3 fever was rarely observed because of our institutional protocol of routinely using scheduled antipyretics to diminish fevers. [Table: see text]

Epirubicin at two dose levels with prednisolone as treatment for advanced breast cancer: the results of a randomized trial.

1991 ◽  
Vol 9 (2) ◽  
pp. 295-304 ◽  
Author(s):  
T Habeshaw ◽  
J Paul ◽  
R Jones ◽  
S Stallard ◽  
M Stewart ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Progressive Disease ◽  
Complete Response ◽  
Median Number ◽  
Symptomatic Improvement ◽  
Advanced Breast ◽  
World Health ◽  
High Dose ◽  
Severe Toxicity

Two hundred eleven patients with advanced breast cancer were randomized to receive either epirubicin (E) 50 mg/m2 and prednisolone (LEP) or E 100 mg/m2 and prednisolone (HEP). The intended treatment consisted of 16 courses of LEP or eight courses of HEP given at 3-weekly intervals. Reasons for stopping treatment early included progressive disease, stable disease without symptomatic improvement, or severe toxicity deemed intolerable by either the patient or physician. Toxicity was recorded at 3-weekly and response at 9-weekly intervals using the World Health Organization (WHO) criteria of response and toxicity. Two hundred nine patients were eligible for analysis, 98% of whom have been followed for more than a year. One hundred four patients received LEP and 105 HEP. Significantly worse myelosuppression, alopecia, nausea and vomiting, and mucositis were seen in the high-dose arm (P less than or equal to .001). More patients in the LEP arm stopped treatment before the fourth course than in the HEP arm, and the commonest reason for stopping was progressive disease. A similar median number of courses was given in each arm. There was a significantly higher response in the HEP arm (HEP - complete response [CR] + partial response [PR] = 41%, LEP - CR + PR = 23%). Despite this, no statistically significant differences was seen in overall survival or progression-free interval. The median survival for HEP and LEP was 44 and 46 weeks, respectively.

Cisplatin, Dacarbazine With or Without Subcutaneous Interleukin-2, and Interferon Alfa-2b in Advanced Melanoma Outpatients: Results From an Italian Multicenter Phase III Randomized Clinical Trial

2002 ◽  
Vol 20 (6) ◽  
pp. 1600-1607 ◽  
Author(s):  
Ruggero Ridolfi ◽  
Vanna Chiarion-Sileni ◽  
Michele Guida ◽  
Antonella Romanini ◽  
Roberto Labianca ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Randomized Clinical Trial ◽  
Low Dose ◽  
Interleukin 2 ◽  
Advanced Melanoma ◽  
Interferon Alfa ◽  
Phase Iii ◽  
World Health ◽  
High Dose ◽  
Severe Toxicity

PURPOSE: Phase II and III studies have shown that the addition of interleukin-2 (IL-2) and interferon alfa-2b (IFNα-2b) in multiagent chemotherapy (CT) for advanced melanoma increases overall response (OR), albeit without clear evidence of an improvement in overall survival (OS). Treatment with high-dose IL-2 can cause severe toxicity and is normally administered in an inpatient setting. We conducted a multicenter prospective randomized clinical trial in outpatients with metastatic melanoma to compare CT with biochemotherapy (bioCT) using immunomodulant doses of IL-2 and IFNα-2b. PATIENTS AND METHODS: One hundred seventy-six eligible patients with advanced melanoma were randomized to receive CT (cisplatin and dacarbazine with or without carmustine every 21 days) or bioCT comprising the same CT regimen followed by low-dose subcutaneous IL-2 for 8 days and IFNα2b three times a week, both for six cycles. RESULTS: At a median follow-up of 18 (CT) and 16 (bioCT) months, median OS was 9.5 versus 11.0 months (P = .51), respectively. In the 89 CT-arm patients, 18 ORs (20.2%) (three complete responders [CRs] and 15 partial responders [PRs]) were observed according to World Health Organization criteria. In the 87 bioCT-arm patients, 22 ORs (25.3%) (three CRs and 19 PRs) (P = .70) were recorded. Treatment-related toxicity was fairly similar in both arms. CONCLUSION: The addition of low-dose immunotherapy did not produce a statistically significant advantage in OS, time to progression, or OR. However, the 11-month median OS in the bioCT arm does not differ greatly from the best results with high-dose IL-2–containing regimens reported in the literature. Furthermore, our treatment schedule was carried out on outpatients and had an acceptable level of toxicity.

scholarly journals 858 TILKine-2: a novel best-in-class tumor infiltrating lymphocyte (TIL) targeting engineered IL-2 with superior pre-clinical efficacy and safety for immunotherapy of cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A899-A899
Author(s):  
Sreerupa Challa ◽  
Jonathan Carnino ◽  
Andrea Umana ◽  
Yuesheng Li ◽  
Jing Xu ◽  
...  
Keyword(s):  
Nk Cells ◽  
Half Life ◽  
Intracellular Signaling ◽  
Functional Characterization ◽  
Interleukin 2 ◽  
Systemic Toxicity ◽  
Fine Tuning ◽  
Therapeutic Window ◽  
High Dose ◽  
Severe Toxicity

BackgroundHigh-dose Interleukin-2 is the earliest FDA-approved immunotherapy for metastatic melanoma and renal cell carcinoma. Unfortunately, its application is limited due to its short half-life and severe toxicity at the therapeutic dose. To limit systemic toxicity, tumor-targeting antibody-based delivery of IL-2 has been developed, however with poor outcomes. We here deploy a novel strategy to deliver IL-2 to the tumor microenvironment by binding to Tumor-Infiltrating Lymphocytes (TILs). TILKine-2 is a recombinant bifunctional protein comprised of an antibody directed against TILs (TILAb) fused to an engineered IL-2, which simultaneously revives and expands antigen-primed exhausted T cells. The IL-2 portion of TILKine-2 was engineered to have improved tolerability, slower receptor-mediated clearance, and prolonged half-life.MethodsTarget binding of TILKine-2 was evaluated by cell-free and cell-based methods. In vitro functional characterization was performed using human peripheral blood mononuclear cells (PBMCs). Pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of murine TILKine-2 surrogate (TILKine-2s) were evaluated in various syngeneic models. The safety and immune cell activation of TILKine-2 were assessed in non-human primates (NHPs).ResultsStructure-based design and activity-guided fine-tuning resulted in an optimized IL-2 variant that was fused to TILAb to generate TILKine-2. TILKine-2 demonstrated TIL-target antigen binding and blocking activity with sub-nM potency. TILKine-2 has a binding activity abolished to IL-2Rα and fine-tuned to IL-2Rβγ. In PBMCs, TILKine-2 potently induced intracellular signaling and cell proliferation in IL-2Rβγ dominant effector CD8+T and NK cells along with IFN-γ secretion. In vivo, TILKine-2 displayed significantly prolonged half-life with sustained proliferation, expansion, and Granzyme B expression on CD8+T and NK cells. Notably, the effects were more pronounced in the tumor than periphery, leading to massive immune hot tumors. Consequently, TILKine-2s exhibited robust anti-tumor primary and memory response in both cold and hot tumor models (MC38, CT26, B16F10, PAN02). Furthermore, TILKine-2s demonstrated superior and synergistic anti-tumor efficacy compared to TILAb alone, engineered IL-2 alone, or their combination, with 100% tumor regression resulting in ~80% tumor free mice in MC38 and Pan02 models. In NHPs, TILKine-2 preferentially induced memory CD8+T, total CD8+T, and NK cell expansion. TILKine-2 was safe and well-tolerated in NHPs with no notable changes in body weight, temperature, clinical pathology, or signs of vascular leakage after repeated dosing.ConclusionsBy targeting TILs, TILKine-2 demonstrated robust anti-tumor efficacy by preferentially inducing proliferation, expansion, and activation of intra-tumoral lymphocytes while reducing systemic toxicity and improving therapeutic window. In conclusion, TILKine-2 is a promising therapeutic agent for clinical development.Ethics ApprovalFor mouse studies, the practices and procedures used were reviewed and approved by Brandeis University IACUC committee (Protocol #22001). For monkey studies, the practices and procedures used were in accordance with the safety and Quality Assurance guidelines set out in the Guideline for Experiments document of Kunming Biomed International (KBI--01-GEv2.0).

scholarly journals Factors Influencing the Efficacy of Anti-PD-1 Therapy in Chinese Patients with Advanced Melanoma

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Lingdi Zhao ◽  
Yonghao Yang ◽  
Baozhen Ma ◽  
Wei Li ◽  
Tiepeng Li ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Univariate Analysis ◽  
Objective Response ◽  
Eastern Cooperative Oncology Group ◽  
Cox Proportional Hazards ◽  
Advanced Melanoma ◽  
Chinese Patients ◽  
Time To Progression ◽  
Independent Predictive Factor ◽  
Factors Influencing

Purpose. Anti-PD-1 antibody improves the survival of patients with advanced melanoma. However, the efficacy and safety of anti-programmed death protein 1 (PD-1) antibody have not been fully elucidated in Chinese melanoma patients, who show high frequency of mucosal and acral melanoma subtypes; besides, the factors influencing the efficacy of anti-PD-1 antibody have not been evaluated broadly. Patients and Methods. Patients with advanced melanoma treated with regimens containing anti-PD-1 antibody from June 2016 to January 2019 were evaluated. Baseline characteristics and blood parameters were assessed, and outcome and adverse events were evaluated according to different regimens. The Cox proportional hazards regression model was used for univariate and multivariate analyses. Results. A total of 51 patients with advanced melanoma were included in this study. The overall objective response rate (ORR) was 17.6%, the disease control rate was 58.5%, and the median time to progression was 5.2 months. The ORR of patients with PD-1 blockade-based combination therapy, without liver metastases and higher level of C-reactive protein (CRP) before PD-1 blockade, is higher than that of those not. Univariate analysis based on clinical features showed that ECOG scores, liver metastasis, elevated lactate dehydrogenase (LDH), and CRP levels were the factors affecting time to progression (TTP). Multivariate analysis showed that elevated CRP before PD-1 blockade was an independent predictive factor for ORR of PD-1 blockade therapy (P=0.009), while only Eastern Cooperative Oncology Group (ECOG) score was an independent predictor for TTP (P=0.032). The treatment was well tolerated in these cohort patients, and there was no treatment-related death. Conclusion. Anti-PD-1 antibody-containing regimen was safe and effective in Chinese patients with advanced melanoma, and elevated CRP and ECOG score were independent factors predicting the efficacy of anti-PD-1 therapy.

Randomized placebo-controlled clinical trial of high-dose interleukin-2 in combination with a soluble p75 tumor necrosis factor receptor immunoglobulin G chimera in patients with advanced melanoma and renal cell carcinoma.

1997 ◽  
Vol 15 (3) ◽  
pp. 1052-1062 ◽  
Author(s):  
J S Du Bois ◽  
E G Trehu ◽  
J W Mier ◽  
L Shapiro ◽  
M Epstein ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tumor Necrosis Factor ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Tumor Necrosis ◽  
Interleukin 2 ◽  
Advanced Melanoma ◽  
High Dose ◽  
Biologic Effects ◽  
Necrosis Factor

PURPOSE A randomized, double-blind, placebo-controlled trial was performed to compare the toxicity and biologic effects of treatment with high-dose intravenous (IV) bolus interleukin-2 (IL-2) plus the recombinant human soluble p75 tumor necrosis factor (TNF) receptor immunoglobulin G (IgG) chimera (rhuTNFR:Fc) with high-dose IL-2 alone in patients with advanced melanoma and renal cell carcinoma. PATIENTS AND METHODS Twenty patients with advanced melanoma or renal cell carcinoma were randomized to receive IL-2 (Chiron, Emeryville, CA) 600,000 IU/kg every 8 hours on days 1 to 5 and 15 to 19 (maximum, 28 doses) combined with placebo or the rhuTNFR:Fc fusion protein (Immunex, Seattle, WA) 10 mg/m2 on days 1 and 15 and 5 mg/m2 on days 3, 5, 17, and 19. The impact of rhuTNFR:Fc on IL-2 toxicity and biologic effects was evaluated. RESULTS No clinically significant difference in toxicity was observed in the two treatment arms. The adjusted median number of IL-2 doses administered during cycle 1 was 24.5 (range, seven to 28) and 21.5 (range, five to 27) for the placebo and rhuTNFR:Fc arms, respectively (P = .544). IL-2-induced TNF bioactivity, neutrophil chemotactic defect, and serum IL-6, IL-8, and IL-1 receptor antagonist (IL-1RA) induction were suppressed by rhuTNFR:Fc. Two of nine assessable patients (22%) on IL-2/placebo and three of 10 patients (30%) on IL-2/rhuTNFR:Fc responded. CONCLUSION Despite evidence of in vitro neutralization of TNF functional activity and partial inhibition of other secondary biologic effects of IL-2, rhuTNFR:Fc does not reduce the clinical toxicity associated with high-dose IL-2 therapy. These results suggest that the toxicity and antitumor effects of IL-2 treatment are independent of circulating TNF.

scholarly journals High-Dose Ipilimumab and High-Dose Interleukin-2 for Patients With Advanced Melanoma

2020 ◽  
Vol 9 ◽  
Author(s):  
Ann W. Silk ◽  
Howard L. Kaufman ◽  
Brendan Curti ◽  
Janice M. Mehnert ◽  
Kim Margolin ◽  
...  
Keyword(s):  
Interleukin 2 ◽  
Advanced Melanoma ◽  
High Dose

scholarly journals Three Phase II Cytokine Working Group Trials of gp100 (210M) Peptide Plus High-Dose Interleukin-2 in Patients With HLA-A2–Positive Advanced Melanoma

2008 ◽  
Vol 26 (14) ◽  
pp. 2292-2298 ◽  
Author(s):  
Jeffrey A. Sosman ◽  
Carole Carrillo ◽  
Walter J. Urba ◽  
Lawrence Flaherty ◽  
Michael B. Atkins ◽  
...  
Keyword(s):  
Phase Ii ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
Advanced Melanoma ◽  
Phase Iii ◽  
Clinical Activity ◽  
High Dose ◽  
Phase Ii Trials ◽  
Cell Immunity ◽  
Three Phase

Purpose High-dose interleukin-2 (IL-2) induces responses in 15% to 20% of patients with advanced melanoma; 5% to 8% are durable complete responses (CRs). The HLA-A2–restricted, modified gp100 peptide (210M) induces T-cell immunity in vivo and has little antitumor activity but, combined with high-dose IL-2, reportedly has a 42% (13 of 31 patients) response rate (RR). We evaluated 210M with one of three different IL-2 schedules to determine whether a basis exists for a phase III trial. Patients and Methods In three separate phase II trials, patients with melanoma received 210M subcutaneously during weeks 1, 4, 7, and 10 and standard high-dose IL-2 during weeks 1 and 3 (trial 1), weeks 7 and 9 (trial 2), or weeks 1, 4, 7, and 10 (trial 3). Immune assays were performed on peripheral-blood mononuclear cells collected before and after treatment. Results From 1998 to 2003, 131 patients with HLA-A2–positive were enrolled. With 60-month median follow-up time, the overall RR for 121 assessable patients was 16.5% (95% CI, 10% to 26%); the RRs were 23.8% in trial 1 (42 patients), 12.5% in trial 2 (40 patients), and 12.8% in trial 3 (39 patients). There were 11 CRs (9%) and nine partial responses (7%), with 11 patients (9%) progression free at ≥ 30 months. Immune studies including assays of CD3-ζ expression and numbers of CD4+/CD25+/FoxP3+ regulatory T cells, CD15+/CD11b+/CD14– immature myeloid-derived cells, and CD8+gp100 tetramer-positive cells in the blood did not correlate with clinical benefit. Conclusion The results again demonstrate efficacy of high-dose IL-2 in advanced melanoma but did not demonstrate the promising clinical activity reported with vaccine and high-dose IL-2 in any of three phase II trials.

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