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

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.2007.13.3165 ◽

2008 ◽

Vol 26 (14) ◽

pp. 2292-2298 ◽

Cited By ~ 79

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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Phase II trial of high-dose interleukin-2 (IL-2) with priming and concomitant sargramostim (GM-CSF) in patients with advanced melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2010.28.15_suppl.8560 ◽

2010 ◽

Vol 28 (15_suppl) ◽

pp. 8560-8560 ◽

Cited By ~ 2

Author(s):

J. Lutzky ◽

D. H. Lawson ◽

Y. Enriquez-Nunez ◽

D. Gabrilovich

Keyword(s):

Phase Ii ◽

Phase Ii Trial ◽

Interleukin 2 ◽

Advanced Melanoma ◽

High Dose ◽

Gm Csf

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

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.9075 ◽

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).

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Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma

Journal of Clinical Oncology ◽

10.1200/jco.21.00612 ◽

2021 ◽

pp. JCO.21.00612

Author(s):

Amod A. Sarnaik ◽

Omid Hamid ◽

Nikhil I. Khushalani ◽

Karl D. Lewis ◽

Theresa Medina ◽

...

Keyword(s):

Disease Control ◽

Metastatic Melanoma ◽

Treatment Options ◽

Objective Response ◽

Interleukin 2 ◽

Advanced Melanoma ◽

Disease Control Rate ◽

High Dose ◽

Tumor Infiltrating Lymphocyte ◽

Programmed Death

PURPOSE Effective treatment options are limited for patients with advanced (metastatic or unresectable) melanoma who progress after immune checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes has demonstrated efficacy in advanced melanoma. Lifileucel is an autologous, centrally manufactured tumor-infiltrating lymphocyte product. METHODS We conducted a phase II open-label, single-arm, multicenter study in patients with advanced melanoma who had been previously treated with checkpoint inhibitor(s) and BRAF ± MEK targeted agents. Lifileucel was produced from harvested tumor specimens in central Good Manufacturing Practice facilities using a streamlined 22-day process. Patients received a nonmyeloablative lymphodepletion regimen, a single infusion of lifileucel, and up to six doses of high-dose interleukin-2. The primary end point was investigator-assessed objective response rate (ORR) per RECIST, version 1.1. RESULTS Sixty-six patients received a mean of 3.3 prior therapies (anti–programmed death 1 [PD-1] or programmed death ligand 1 [PD-L1]: 100%; anticytotoxic T-lymphocyte-associated protein-4: 80%; BRAF ± MEK inhibitor: 23%). The ORR was 36% (95% CI, 25 to 49), with two complete responses and 22 partial responses. Disease control rate was 80% (95% CI, 69 to 89). Median duration of response was not reached after 18.7-month median study follow-up (range, 0.2-34.1 months). In the primary refractory to anti–PD-1 or PD-L1 therapy subset, the ORR and disease control rate were 41% (95% CI, 26 to 57) and 81% (95% CI, 66 to 91), respectively. Safety profile was consistent with known adverse events associated with nonmyeloablative lymphodepletion and interleukin-2. CONCLUSION Lifileucel demonstrated durable responses and addresses a major unmet need in patients with metastatic melanoma with limited treatment options after approved therapy, including the primary refractory to anti–PD-1 or PD-L1 therapy subset.

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

Journal of Clinical Oncology ◽

10.1200/jco.1990.8.7.1138 ◽

1990 ◽

Vol 8 (7) ◽

pp. 1138-1147 ◽

Cited By ~ 58

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.

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A Cytokine Working Group (CWG) 3-arm phase II trial of gp100 (209–2M) peptide + high dose (HD) Interleukin-2 (IL-2) in HLA-A2+ (A2+) advanced melanoma patients (pts)

Journal of Clinical Oncology ◽

10.1200/jco.2005.23.16_suppl.7504 ◽

2005 ◽

Vol 23 (16_suppl) ◽

pp. 7504-7504 ◽

Cited By ~ 3

Author(s):

M. Ernstoff ◽

C. Carrillo ◽

W. Urba ◽

L. Flaherty ◽

J. Clark ◽

...

Keyword(s):

Phase Ii ◽

Working Group ◽

Phase Ii Trial ◽

Interleukin 2 ◽

Advanced Melanoma ◽

High Dose ◽

Melanoma Patients

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Quality of life in patients with advanced melanoma receiving vaccine therapy alone (V) or vaccine with high-dose interleukin-2 (V-HIL2)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.8549 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 8549-8549

Author(s):

S. F. Marden ◽

P. Muehlbauer ◽

K. Soeken ◽

N. Kline Leidy ◽

D. Parchen ◽

...

Keyword(s):

Quality Of Life ◽

Short Form ◽

Interleukin 2 ◽

Well Being ◽

Advanced Melanoma ◽

Response To Therapy ◽

Health Concern ◽

High Dose

8549 Background: Melanoma is a public health concern with 1 in 75 Americans diagnosed during their lifetime and 5-year survival rate of about 10% for those with advanced melanoma. With curative options limited, new regimens must be evaluated and attention given to outcomes of how patients feel and function as a result of therapy. Methods: We examined the effect of biotherapy and fatigue on health-related quality of life (HRQL) in patients with stage IV melanoma enrolled in phase II clinical trials at the NCI receiving peptide vaccines with or without high dose IL-2. Generic HRQL was measured by physical (PCS) and mental (MCS) summary scores of the Short Form-36 health survey (SF-36). The Functional Assessment of Cancer Therapy-General (FACT-G) with a fatigue scale (FS) measured disease-specific HRQL and fatigue. Higher scores on measures indicate better physical, emotional, social function and well-being and less fatigue. Between 2000–2003, patients (F=22, M=47; mean age 46 ± 11) completed measures by computer at baseline (BL) and first follow-up after 2 cycles of treatment, before discussion of response to therapy. Data were analyzed using two-way ANCOVA with biotherapy (V or V-HIL2) and fatigue (worse (W) or improved/stable (I/S)) as factors and BL HRQL as covariate. A clinically important difference on FS is reported as 3 points. Fatigue levels with decrease of 3 from BL to follow-up were classified as W and <3 as I/S. Results: Patients were Caucasian (99%), married (77%), BL ECOG 0 or 1 (99%), mean BL Hgb 13 ± 2 and received 2 prior therapies (38%) or more (42%). Adjusting for BL HRQL, there was no biotherapy (p >.30) or interaction effect (p >.60; table ). There was a fatigue effect (p <.001) with lower HRQL adjusted mean scores in W versus I/S. Conclusions: HRQL does not differ in patients with advanced melanoma ECOG 0 or 1 who receive investigational V versus V-HIL2 at follow-up evaluation. Patients’ reporting of worsened fatigue is associated with poorer HRQL, regardless of the biotherapy received. [Table: see text] [Table: see text]

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