A phase II study of interleukin-2 and lymphokine-activated killer cells in patients with metastatic malignant melanoma.

1989 ◽  
Vol 7 (4) ◽  
pp. 477-485 ◽  
Author(s):  
J P Dutcher ◽  
S Creekmore ◽  
G R Weiss ◽  
K Margolin ◽  
A B Markowitz ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Adoptive Immunotherapy ◽  
Interleukin 2 ◽  
Response Duration ◽  
Lak Cells ◽  
High Dose ◽  
Cardiac Events ◽  
Lymphokine Activated Killer Cells ◽  
Median Response ◽  
Subcutaneous Nodules

Thirty-six patients with metastatic melanoma were entered into a study of the therapeutic efficacy of adoptive immunotherapy with high-dose interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells. Thirty-two patients who received all components of the therapy are evaluable for response, and all patients are evaluable for toxicity. Sites of disease included lung, liver, subcutaneous nodules, and intra-abdominal metastases. One complete response (CR) and five partial responses (PRs) resulted from treatment (19% response rate). The median response duration was 5 months, with the durable CR continuing at 31+ months and one durable PR continuing for 13 months. Sites of response included lung, liver, subcutaneous nodules, and lymph nodes. Response, response duration, or site of response did not correlate with the total dose of IL-2 administered, rebound lymphocytosis, or the number of LAK cells infused. Toxicity included hypotension, fluid retention with a "capillary leak syndrome" in most patients, and transient multiorgan dysfunction that resolved promptly after the completion of therapy. Adverse cardiac events occurred in 16% of patients, with one myocardial infarction leading to a death. This study confirms the activity of the initial IL-2/LAK cell regimen in metastatic melanoma reported by Rosenberg et al, supporting the concept of adoptive immunotherapy as an important new treatment approach for this disease.

High-Dose Recombinant Interleukin 2 Therapy for Patients With Metastatic Melanoma: Analysis of 270 Patients Treated Between 1985 and 1993

1999 ◽  
Vol 17 (7) ◽  
pp. 2105-2105 ◽  
Author(s):  
Michael B. Atkins ◽  
Michael T. Lotze ◽  
Janice P. Dutcher ◽  
Richard I. Fisher ◽  
Geoffrey Weiss ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Performance Status ◽  
Objective Response ◽  
Interleukin 2 ◽  
Response Duration ◽  
High Dose ◽  
Large Tumor ◽  
Median Response ◽  
Recombinant Interleukin 2 ◽  
Prior Systemic Therapy

PURPOSE: To determine the short- and long-term efficacy and toxicity of the high-dose intravenous bolus interleukin 2 (IL-2) regimen in patients with metastatic melanoma. PATIENTS AND METHODS: Two hundred seventy assessable patients were entered onto eight clinical trials conducted between 1985 and 1993. IL-2 (Proleukin [aldesleukin]; Chiron Corp, Emeryville, CA) 600,000 or 720,000 IU/kg was administered by 15-minute intravenous infusion every 8 hours for up to 14 consecutive doses over 5 days as clinically tolerated with maximum support, including pressors. A second identical treatment cycle was scheduled after 6 to 9 days of rest, and courses could be repeated every 6 to 12 weeks in stable or responding patients. Data were analyzed through fall 1996. RESULTS: The overall objective response rate was 16% (95% confidence interval, 12% to 21%); there were 17 complete responses (CRs) (6%) and 26 partial responses (PRs) (10%). Responses occurred with all sites of disease and in patients with large tumor burdens. The median response duration for patients who achieved a CR has not been reached and was 5.9 months for those who achieved a PR. Twelve (28%) of the responding patients, including 10 (59%) of the patients who achieved a CR, remain progression-free. Disease did not progress in any patient responding for more than 30 months. Baseline performance status and whether patients had received prior systemic therapy were the only predictive prognostic factors for response to IL-2 therapy. Toxicities, although severe, generally reversed rapidly after therapy was completed. Six patients (2%) died from adverse events, all related to sepsis. CONCLUSION: High-dose IL-2 treatment seems to benefit some patients with metastatic melanoma by producing durable CRs or PRs and should be considered for appropriately selected melanoma patients.

A phase II study of high-dose continuous infusion interleukin-2 with lymphokine-activated killer cells in patients with metastatic melanoma.

1991 ◽  
Vol 9 (4) ◽  
pp. 641-648 ◽  
Author(s):  
J P Dutcher ◽  
E R Gaynor ◽  
D H Boldt ◽  
J H Doroshow ◽  
M H Bar ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Metastatic Melanoma ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Interleukin 2 ◽  
Lak Cells ◽  
High Dose ◽  
Lymphokine Activated Killer Cells ◽  
Lak Cell

Thirty-three patients with metastatic melanoma were treated in a phase II study with an intravenous continuous infusion (IVCI) of interleukin-2 (IL2) given with lymphokine-activated killer (LAK) cells. The dose of IL2 was the optimal priming dose for LAK-cell induction, followed by the maximally tolerated LAK-cell dose that could be given by an IVCI schedule as determined by a previous phase I trial. The CI schedule was chosen for evaluation because of a postulated reduction in toxicity with the possibility of administering a more prolonged IL2 infusion and because greater rebound lymphocytosis and LAK-cell generation had been reported using this dose and schedule. The 33 patients were similar in age, performance status, and sites of disease to those treated in previous IL2 trials. All patients were assessable for response and toxicity. One patient (3%) achieved a partial response of 10 months duration. There were no other clinically significant responses. Significant toxicity included hypotension requiring pressors (45%), dyspnea (36%), renal insufficiency (24%), hepatic dysfunction (66%), and cardiac arrhythmias (18%). These toxicities reversed with cessation of the infusion. There were four deaths during the first 30 days of treatment, three from infection (one related to central line, one related to LAK cells, one related to tumor), and one from tumor-related hemorrhage. Toxicity was unexpectedly high and at least comparable to that seen in previous studies using a high-dose IV bolus schedule of IL2. When comparing the IVCI schedule with high-dose bolus IL2 to LAK cells in nonrandomized but sequential studies in patients with advanced melanoma, it appears that CI IL2 is less efficacious.

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.

Interleukin-2 therapy in patients with metastatic malignant melanoma: a phase II study.

1990 ◽  
Vol 8 (10) ◽  
pp. 1650-1656 ◽  
Author(s):  
D R Parkinson ◽  
J S Abrams ◽  
P H Wiernik ◽  
A A Rayner ◽  
K A Margolin ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Phase Ii ◽  
Single Agent ◽  
Interleukin 2 ◽  
Response Duration ◽  
Metastatic Malignant Melanoma ◽  
Lak Cells ◽  
Previous Trial ◽  
Eligibility Criteria ◽  
Median Response

Forty-seven patients with metastatic malignant melanoma were treated with two 5-day cycles of 100,000 U/kg recombinant interleukin-2 (IL-2) intravenously (IV) every 4 hours separated by 1 week. This dose and schedule of IL-2 were identical to those used in a previous combined IL-2 and lymphokine-activated killer (LAK) cell phase II clinical trial of the IL-2/LAK Working Group. Patient eligibility criteria, and clinical management guidelines were similar to those used in the previous trial. Forty-six patients were assessable for response. Objective responses were observed in 10 of 46 patients (two complete responses [CRs], eight partial responses [PRs]) or 22% with responses occurring in lung and liver as well as lymph nodes and subcutaneous sites. The median response duration was 8 months. Toxicity was significant; three patients developed myocardial infarction, and one patient died during therapy. Overall the toxicity and response rate for single-agent IL-2 are similar to that observed with IL-2 administered in combination with LAK cells in the previous trial. These results suggest that single-agent therapy with IL-2 when administered in this schedule has significant antimelanoma activity in humans, and that LAK cells generated from peripheral blood add little to the antimelanoma activity of this dose and schedule of IL-2.

scholarly journals Long-term progression-free survival of patients with metastatic melanoma or renal cell carcinoma following high-dose interleukin-2

2021 ◽  
Vol 69 (4) ◽  
pp. 888-892
Author(s):  
Joseph I Clark ◽  
Brendan Curti ◽  
Elizabeth J Davis ◽  
Howard Kaufman ◽  
Asim Amin ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Melanoma ◽  
Systemic Therapy ◽  
Renal Cell ◽  
Interleukin 2 ◽  
Progression Free Survival ◽  
High Dose ◽  
Free Survival

High-dose interleukin-2 (HD IL-2) was approved in the 1990s after demonstrating durable complete responses (CRs) in some patients with metastatic melanoma (mM) and metastatic renal cell carcinoma (mRCC). Patients who achieve this level of disease control have also demonstrated improved survival compared with patients who progress, but limited data are available describing the long-term course. The aim of this study was to better characterize long-term survival following successful HD IL-2 treatment in patients with no subsequent systemic therapy. Eleven HD IL-2 treatment centers identified patients with survival ≥5 years after HD IL-2, with no subsequent systemic therapy. Survival was evaluated from the date of IL-2 treatment to June 2017. Treatment courses consisted of 2 1-week cycles of HD IL-2. Patients were treated with HD IL-2 alone, or HD IL-2 followed by local therapy to achieve maximal response. 100 patients are reported: 54 patients with mM and 46 patients with mRCC. Progression-free survival (PFS) after HD IL-2 ranges from 5+ years to 30+ years, with a median follow-up of 10+ years. 27 mRCC and 32 mM are alive ≥10 years after IL-2. Thus, a small subset of patients with mM and mRCC achieve long-term PFS (≥5 years) after treatment with HD IL-2 as their only systemic therapy. The ability of HD IL-2 therapy to induce prolonged PFS should be a major consideration in studies of new immunotherapy combinations for mM and mRCC.

Long-Term Follow-up of Patients with Recurrent Malignant Gliomas Treated with Adjuvant Adoptive Immunotherapy

Neurosurgery ◽  
1991 ◽  
Vol 28 (1) ◽  
pp. 16-23 ◽  
Author(s):  
Kevin O. Lillehei ◽  
Dawn H. Mitchell ◽  
Stephen D. Johnson ◽  
Larry E. McCleary ◽  
Carol A. Kruse
Keyword(s):  
Survival Time ◽  
Adoptive Immunotherapy ◽  
Peripheral Blood ◽  
Interleukin 2 ◽  
Peripheral Blood Lymphocytes ◽  
Lak Cells ◽  
Prior Chemotherapy ◽  
Blood Lymphocytes ◽  
Significant Difference

Abstract Between August 1986 and October 1987, the Denver Brain Tumor Research Group conducted a clinical trial using autologous human recombinant interleukin-2 (rIL-2)-activated lymphocytes to treat 20 patients with recurrent high-grade gliomas. The trial involved surgical resection and/or decompression followed by intracavitary implantation of lymphokine-activated killer (LAK) cells and autologous stimulated lymphocytes (ASL) along with rIL-2 in a plasma clot. One month later, stimulated lymphocytes and rIL-2 were infused through a Rickham reservoir attached to a catheter directed into the tumor bed. The LAK cells were rIL-2-activated peripheral blood lymphocytes cultured for 4 days; the ASL were lectin- and rIL-2-activated peripheral blood lymphocytes cultured for 10 days. Of the 20 patients treated, 11 were evaluated as a group (mean age, 44 years, range, 15-61 years; mean Karnofsky rating, 69, range, 50-100; mean Decadron dose at entry, 14 mg/d. range, 0-32). The average number of lymphocytes implanted was 7.6 × 109 (range, 1.9-27.5 × 109), together with 1 to 4 × 106 U of rIL-2. To date, 10 of the 11 patients died, all from recurrent tumor growth. The median overall survival time was 63 weeks (range, 36-201; mean, 86). The median survival time after immunotherapy was 18 weeks (range, 11-151; mean, 39). No significant difference in survival after immunotherapy was found between those patients who had received previous chemotherapy and those who had not. The use of steroids or prior chemotherapy did not influence the in vitro generation of ASL or LAK cells. Prior chemotherapy did correlate, however, with diminished in vitro cytotoxicity against the natural killer-sensitive (K562) target cell by LAK cells (P < 0.05) but not that by ASL. There were no major adverse side effects. Although adoptive immunotherapy was safe and well tolerated, its therapeutic potential remains in question.

Complete regression of subcutaneous and cutaneous metastatic melanoma with high-dose intralesional interleukin 2 in combination with topical imiquimod and retinoid cream

2011 ◽  
Vol 21 (3) ◽  
pp. 235-243 ◽  
Author(s):  
Miki Shirakawa Garcia ◽  
Yoko Ono ◽  
Steve R. Martinez ◽  
Steven L. Chen ◽  
Heidi Goodarzi ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Interleukin 2 ◽  
High Dose ◽  
Complete Regression ◽  
Topical Imiquimod

Preclinical Evaluation of a Bone-Marrow Autograft Culture Procedure for Generating Lymphokine-Activated Killer Cells in Vitro

1992 ◽  
Vol 3 (suppl b) ◽  
pp. 123-127 ◽  
Author(s):  
Hans-Georg Klingemann ◽  
Heather Deal ◽  
Dianne Reid ◽  
Connie J Eaves
Keyword(s):  
Bone Marrow ◽  
Calf Serum ◽  
Cell Activity ◽  
Hematopoietic Cells ◽  
Lak Cells ◽  
High Dose ◽  
Lymphokine Activated Killer Cells ◽  
Lak Cell

Despite the use of high dose chemoradiotherapy for the treatment of acute leukemia. relapse continues to be a major cause of death in patients given an autologous bone marrow transplant. Further augmentation of pretransplant chemotherapy causes life threatening toxicity to nonhematopoietic tissues and the effectiveness of currently available ex vivo purging methods in reducing the relapse rate is unclear. Recently, data from experimental models have suggested that bone marrow-derived lymphokine (IL-2)-activated killer (BM-LAK) cells might be used to eliminate residual leukemic cells both in vivo and in vitro. To evaluate this possibility clinically, a procedure was developed for culturing whole marrow harvests with IL-2 prior to use as autografts, and a number of variables examined that might affect either the generation of BM-LAK cells or the recovery of the primitive hematopoietic cells. The use of Dexter long term culture (LTC) conditions, which expose the cells to horse serum and hydrocortisone. supported LAK cell generation as effectively as fetal calf serum (FCS) -containing medium in seven-day cultures. Maintenance of BM-LAK cell activity after a further seven days of culture in the presence of IL-2 was also tested. As in the clinical setting. patients would receive IL-2 in vivo for an additional week immediately following infusion of the cultured marrow autograft. Generation ofBM-LAK activity was dependent on the presence of IL-2 and could be sustained by further incubation in medium containing IL-2. Primitive hematopoietic cells were quantitated by measuring the number of in vitro colony-forming progenitors produced after five weeks in secondary Dexter-type LTC. Maintenance of these 'LTC-initiating cells' was unaffected by lL-2 in the culture medium. These results suggest that LAK cells can be generated efficien tly in seven-day marrow autograft cultures containing IL-2 under conditions that allow the most primitive human hematopoietic cells currently detectable to be maintained.

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