Immunomodulation of NK/LAK Cells Utilizing Continuous Infusion of High Doses of Recombinant Human Interleukin-2 in the Treatment of Patients with Advanced Cancer

2015 ◽  
pp. 261-270
Author(s):  
Nathaniel Ching ◽  
Kevin Loh ◽  
Clara Ching ◽  
Jeffrey Nakamura ◽  
Reuben Guerrero ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Advanced Cancer ◽  
Interleukin 2 ◽  
Lak Cells ◽  
High Doses

Continuous interleukin-2 and lymphokine-activated killer cells for advanced cancer: a National Biotherapy Study Group trial.

1991 ◽  
Vol 9 (7) ◽  
pp. 1233-1240 ◽  
Author(s):  
R O Dillman ◽  
R K Oldham ◽  
K W Tauer ◽  
D W Orr ◽  
N M Barth ◽  
...  
Keyword(s):  
Intensive Care ◽  
Continuous Infusion ◽  
Advanced Cancer ◽  
Median Survival ◽  
Renal Cell ◽  
Response Rate ◽  
Cell Cancer ◽  
Interleukin 2 ◽  
Lak Cells ◽  
Lymphokine Activated Killer Cells

We conducted a multicenter, phase II trial of continuous-infusion recombinant interleukin-2 (rIL-2) and lymphokine-activated killer (LAK) cells. Patients had advanced cancer, measurable disease, and a good performance level. Treatment included a 5-day continuous infusion of 18 x 10(6) IU/m2/d of rIL-2 followed by 1 day of rest, 4 days of leukapheresis to collect cells for in vitro augmentation of cellular cytotoxicity, and 5 more days of rIL-2 infusion with reinfusion of LAK cells for 3 successive days. Therapy was repeated after 2 weeks. There were 117 patients enrolled: 63% were males, with a median age of 51 years. Eighty-two percent were managed in oncology units, and 18% were in intensive care units. Six patients died within 1 month of initiating therapy. In renal cell carcinoma, the response rate was one of 31 patients (3%), with a median survival of 10.7 months. In melanoma, the response rate was four of 33 patients (12%), with a median survival of 6.1 months. For all other histologies, response rate was three of 53 patients (5%), with a median survival of 7.4 months. All responders were asymptomatic when therapy was initiated. This trial confirms the feasibility of administering continuous rIL-2 and LAK cells outside the intensive care unit environment. Antitumor activity in melanoma was similar to that seen in multicenter trials of bolus rIL-2 and LAK cells. Activity in renal cell cancer was disappointing.

A randomized phase II trial of continuous infusion interleukin-2 or bolus injection interleukin-2 plus lymphokine-activated killer cells for advanced renal cell carcinoma.

1992 ◽  
Vol 10 (2) ◽  
pp. 275-281 ◽  
Author(s):  
G R Weiss ◽  
K A Margolin ◽  
F R Aronson ◽  
M Sznol ◽  
M B Atkins ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Continuous Infusion ◽  
Renal Cell ◽  
Bolus Injection ◽  
Interleukin 2 ◽  
Lak Cells ◽  
Advanced Renal Cell Carcinoma ◽  
High Dose ◽  
Randomized Phase Ii

PURPOSE Since 1985, multiple centers have demonstrated that interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells produce durable anticancer responses in patients with metastatic renal cell carcinoma. High-dose recombinant IL-2 (rIL-2) has been administered by intravenous bolus injection (Rosenberg SA, et al: N Engl J Med 313:1485-1492, 1985) and by continuous intravenous infusion (West WH, et al: N Engl J Med 316:898-905, 1987) combined with lymphokine-activated killer (LAK) cells, with both methods producing responses in patients with advanced renal cell carcinoma. The Extramural IL-2/LAK Working Group has conducted a randomized phase II trial of two intravenous high-dose rIL-2 regimens (bolus three times daily or 24-hour continuous infusion) to determine if either one manifests greater anticancer activity or a more acceptable toxicity profile. PATIENTS AND METHODS Ninety-four patients with measurable advanced renal cell carcinoma were enrolled on this study: 46 to the bolus injection arm and 48 to the continuous infusion arm. On both arms, patients underwent a priming phase of rIL-2 administration, four daily lymphocytaphereses to harvest mononuclear cells that were placed in 3- to 4-day culture for generation of LAK cells, and an rIL-2/LAK coadministration phase. Patients were then observed monthly for evidence of response to this therapy and were offered up to two additional courses of treatment every 3 months if evidence of response was detected. RESULTS Twenty percent of patients on the bolus injection arm experienced objective responses (three complete responses and six partial responses); 15% of patients on the continuous infusion arm responded (two complete responses and five partial responses). Complete responses were durable, persisting for 310+ to 700+ days. The incidence of severe life-threatening toxicities typical of high-dose rIL-2 therapy was similar in both arms (eg, patients with hypotension requiring pressors: bolus 71%, continuous 63%; oliguria less than or equal to 200 mL/8 hours: bolus 65%, continuous 71%). More episodes of fever, infection, and serum alkaline phosphatase elevation were associated with the continuous infusion arm, while more thrombocytopenia occurred on the bolus injection arm. Four patients (three bolus injection, one continuous infusion) died of respiratory and circulatory failure while under treatment. No clinical or laboratory parameter accompanying treatment on either arm was, by univariate or multivariate analysis, associated with an increased likelihood of response. CONCLUSIONS Both methods of high-dose rIL-2/LAK cell administration produce nearly equivalent anticancer activity and toxicity in the treatment of renal cell carcinoma. The ability to predict responding patients based on patient or treatment characteristics is not possible.

Immunotherapy of patients with advanced cancer using tumor-infiltrating lymphocytes and recombinant interleukin-2: a pilot study.

1988 ◽  
Vol 6 (5) ◽  
pp. 839-853 ◽  
Author(s):  
S L Topalian ◽  
D Solomon ◽  
F P Avis ◽  
A E Chang ◽  
D L Freerksen ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Advanced Cancer ◽  
Adoptive Immunotherapy ◽  
Renal Cell ◽  
Interleukin 2 ◽  
Tumor Infiltrating Lymphocytes ◽  
Lak Cells ◽  
Recombinant Interleukin 2 ◽  
Infiltrating Lymphocytes

Clinical investigations using the adoptive transfer of lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) to treat patients with advanced cancer have yielded encouraging results. We have thus sought ways to enhance the effectiveness of adoptive immunotherapy while minimizing its toxic side effects. Murine experiments have identified tumor-infiltrating lymphocytes (TIL) as killer cells more effective than LAK cells and less dependent on adjunctive systemically administered IL-2 to mediate antitumor effects. Accordingly, we performed a pilot protocol to investigate the feasibility and practicality of administering IL-2-expanded TIL to humans with metastatic cancers. Twelve patients, including six with melanoma, four with renal cell carcinoma, one with breast carcinoma, and one with colon carcinoma, were treated with varying doses and combinations of TIL (8.0 X 10(9) to 2.3 X 10(11) cells per patient), IL-2 (10,000 to 100,000 U/kg three times daily to dose-limiting toxicity), and cyclophosphamide (CPM) (up to 50 mg/kg). Two partial responses (PR) to therapy were observed: pulmonary and mediastinal masses regressed in a patient with melanoma, and a lymph node mass regressed in a patient with renal cell carcinoma. One additional patient with breast cancer experienced a partial regression of disease in lymph nodal and cutaneous sites with complete elimination of malignant cells from a pleural effusion, although cutaneous disease recurred at 4 weeks. The toxicities of therapy were similar to those ascribed to IL-2; no toxic effects were directly attributable to TIL infusions. In five of six melanoma patients, TIL demonstrated lytic activity specific for the autologous tumor target in short-term chromium-release assays, distinct from the nonspecific lytic activity characteristic of LAK cells. This study represents an initial attempt to identify and use lymphocyte subsets with enhanced tumoricidal capacity in the adoptive immunotherapy of human malignancies.

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.

Adoptive Immunotherapy of Advanced Cancer with LAK Cells and Different Dosages of Interleukin-2:Analysis of Lymphocyte Subpopulations

1990 ◽  
pp. 721-727
Author(s):  
P. Samoggia ◽  
E. M. Ruggeri ◽  
G. Mariani ◽  
P. Carlini ◽  
G. Salvo ◽  
...  
Keyword(s):  
Advanced Cancer ◽  
Adoptive Immunotherapy ◽  
Interleukin 2 ◽  
Lymphocyte Subpopulations ◽  
Lak Cells

Extended continuous infusion low-dose recombinant interleukin-2 in advanced cancer: prolonged immunomodulation without significant toxicity.

1991 ◽  
Vol 9 (12) ◽  
pp. 2110-2119 ◽  
Author(s):  
M A Caligiuri ◽  
C Murray ◽  
R J Soiffer ◽  
T R Klumpp ◽  
M Seiden ◽  
...  
Keyword(s):  
Nk Cells ◽  
Advanced Cancer ◽  
Low Dose ◽  
Interleukin 2 ◽  
Outpatient Setting ◽  
Lak Cells ◽  
Phase Ii Studies ◽  
Recombinant Interleukin 2

In previous clinical trials, recombinant interleukin-2 (rIL-2) has been infused at high doses over short periods of time to generate lymphokine-activated killer (LAK) cells in vivo. These trials have been limited by severe toxicities, and the immunologic effects of rIL-2 have been transient. The present study was designed to assess the toxicity and immunologic effects of prolonged administration of low doses of rIL-2. In this phase I study, patients with advanced cancer were scheduled to receive intravenous (IV) infusion of rIL-2 without interruption for 3 months in an outpatient setting. Twenty-one patients received rIL-2 at doses ranging from 0.5 x 10(5) to 6.0 x 10(5) U/m2/d. Treatment was extremely well tolerated, and no patient experienced grade 3 or grade 4 toxicity. The lowest dose level (0.5 x 10(5) U/m2/d) did not have demonstrable immunologic activity. At doses of 1.5 x 10(5) and 4.5 x 10(5) U/m2/d, rIL-2 infusion resulted in the specific expansion of natural-killer (NK) cells (sixfold and ninefold increases, respectively, at these two dose levels) without any changes in B cells, T cells, neutrophils, or monocytes. Grade 2 toxicity was observed at the dose of 6.0 x 10(5) U/m2/d, as three patients required interruption of therapy and two patients who completed therapy developed transient hypothyroidism. In patients with increased NK cells, enhancement of non-major histocompatibility complex (MHC)-restricted cytotoxicity and increased generation of LAK cells in vitro were also demonstrated. Therapy with low-dose rIL-2 can be given safely in an uninterrupted fashion for prolonged periods of time in an outpatient setting. This results in selective expansion of NK cells in vivo with minimal toxicity. Further investigation of this schedule for immunomodulation in vivo should be pursued in phase II studies of both malignant and immunodeficient disease states.

A Phase IA/IB Trial of Anti-CD3 Murine Monoclonal Antibody plus Low-Dose Continuous-Infusion Interleukin-2 in Advanced Cancer Patients

1995 ◽  
Vol 17 (2) ◽  
pp. 171-180 ◽  
Author(s):  
Jeffrey A. Sosman ◽  
Catherine Kefer ◽  
Richard I. Fisher ◽  
Cheryl D. Jacobs ◽  
Peggy Pumfery ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Continuous Infusion ◽  
Cancer Patients ◽  
Advanced Cancer ◽  
Low Dose ◽  
Interleukin 2 ◽  
Murine Monoclonal Antibody ◽  
Advanced Cancer Patients

Pharmacokinetics of repeated i.v. bolus administration of high doses of r-met-Hu interleukin-2 in advanced cancer patients

1990 ◽  
Vol 26 (5) ◽  
pp. 355-358 ◽  
Author(s):  
J. P. Sculier ◽  
J. J. Body ◽  
N. Donnadieu ◽  
S. Nejai ◽  
F. Glibert ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Advanced Cancer ◽  
Interleukin 2 ◽  
Bolus Administration ◽  
Advanced Cancer Patients ◽  
High Doses

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.

scholarly journals Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2.

1985 ◽  
Vol 161 (5) ◽  
pp. 1169-1188 ◽  
Author(s):  
S A Rosenberg ◽  
J J Mulé ◽  
P J Spiess ◽  
C M Reichert ◽  
S L Schwarz
Keyword(s):  
Pulmonary Metastases ◽  
Interleukin 2 ◽  
Systemic Administration ◽  
Lak Cells ◽  
Lymphoid Cells ◽  
High Dose ◽  
Antitumor Effects ◽  
Recombinant Interleukin 2 ◽  
High Doses

Incubation of resting lymphoid cells with recombinant interleukin 2 (IL-2) in vitro leads to the generation of lymphokine activated killer (LAK) cells capable of lysing fresh tumor cell suspensions in short-term chromium-release assays. Our previous studies (7) have demonstrated that the injection of LAK cells plus low doses of recombinant IL-2 were capable of inhibiting the growth of pulmonary metastases. We have now explored the ability of high doses of recombinant IL-2, administered systemically, to generate LAK cells in vivo, and to mediate antitumor effects directly. Administration of increasing doses of recombinant IL-2 intraperitoneally resulted in the generation of LAK cells in the spleens of recipient mice. Doses of 100,000 U recombinant IL-2 administered intraperitoneally approximately every 8 h for 5 d were capable of dramatically inhibiting established 3-d pulmonary metastases from the MCA-105 and MCA-106 syngeneic sarcomas and the syngeneic B16 melanoma in C57BL/6 mice. Grossly visible metastases present at 10 d after tumor injection also underwent regression following IL-2 therapy. Surprisingly, established 10 d pulmonary metastases were more susceptible to the effects of IL-2 than were the smaller 3 d pulmonary metastases. All antitumor effects of the systemic administration of recombinant IL-2 were eliminated if mice received prior treatment with 500 rad total body irradiation. The administration of high doses of recombinant IL-2 was also capable of inhibiting the growth of 3-d established subcutaneous tumors from the MCA-105 sarcoma, and of mediating the inhibition of growth and regression of established palpable subcutaneous MCA-105 sarcomas. Lymphocytes, which appeared morphologically to be activated, were present at the site of regressing tumor, and it appears that the mechanism of the antitumor effect of recombinant IL-2 administered systemically is via the generation of LAK cells in vivo, although this hypothesis remains to be proven. The ready availability of high doses of recombinant human IL-2, and the demonstration of antitumor effects seen in animal models have led us to the initiation of the clinical trials of recombinant IL-2 in humans.

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