Interleukin-2 and lymphokine-activated killer cells in 15 children with advanced metastatic neuroblastoma.

1991 ◽  
Vol 9 (8) ◽  
pp. 1363-1370 ◽  
Author(s):  
S Negrier ◽  
J Michon ◽  
D Floret ◽  
E Bouffet ◽  
J C Gentet ◽  
...  
Keyword(s):  
Day Treatment ◽  
Autologous Bone Marrow Transplantation ◽  
Interleukin 2 ◽  
Rest Period ◽  
Autologous Bone Marrow ◽  
Lak Cells ◽  
Severe Toxicity ◽  
Lymphokine Activated Killer Cells ◽  
End Stage

A phase II trial using interleukin-2 (IL2) and lymphokine-activated killer (LAK) cells was carried out in an attempt to treat children with end-stage neuroblastoma. Fifteen patients (median age, 7 years) were enrolled in the study. Twelve were in relapse after massive chemotherapy and autologous bone marrow transplantation (ABMT), and three had a primary refractory disease after conventional chemotherapy. IL2 was administered as an 18 x 10(6) IU/m2/d continuous infusion. One course consisted of a double 5-day treatment period separated by a 6-day break. Cytapheresis to harvest LAK progenitor cells was performed during the rest period. After a 4-day in vitro culture, LAK cells were reinjected during the second cycle of therapy. A phenotypic and functional analysis of immunologic parameters was conducted along with the therapeutic protocol. Toxicity was significant with two toxic deaths (cardiotoxicity and respiratory distress). The reinfusion of large amounts of LAK cells was clearly involved in one case, but this particularly severe toxicity has to be related to the patient's status (ie, heavy pretreatment). No significant clinical response was seen. The immunologic monitoring showed phenotypic and functional modifications in these patients before initiation of treatment and an unexpected absence of evolution of these parameters during IL2 therapy. Although the origin of these immune dysfunctions is not clear, they could be involved in the failure of IL2 therapy. Future studies of IL2 therapy in neuroblastoma should be undertaken earlier in the course of the disease.

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.

Autologous Bone Marrow Purging with Lak Cells

1993 ◽  
Vol 16 (5_suppl) ◽  
pp. 108-110 ◽  
Author(s):  
L. Giuliodori ◽  
L. Moretti ◽  
S. Stramigioli ◽  
F. Luchetti ◽  
G.M. Annibali ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
Lak Cells ◽  
Marrow Purging ◽  
Autologous Bone ◽  
A Minor ◽  
Bone Marrow Purging

In this study we will demonstrate that LAK cells, in vitro, can lyse hematologic neoplastic cells with a minor toxicity of the staminal autologous marrow cells. In fact, after bone marrow and LAK co-culture at a ratio of 1/1 for 8 hours, the inhibition on the GEMM colonies resulted to be 20% less compared to the untreated marrow. These data make LAK an inviting agent for marrow purging in autologous bone marrow transplantation.

In vitro cytolysis of primitive neuroectodermal tumors of the posterior fossa (medulloblastoma) by lymphokine-activated killer cells

1988 ◽  
Vol 69 (3) ◽  
pp. 403-409 ◽  
Author(s):  
Richard E. George ◽  
William G. Loudon ◽  
Richard P. Moser ◽  
Janet M. Bruner ◽  
Peter A. Steck ◽  
...  
Keyword(s):  
Posterior Fossa ◽  
Interleukin 2 ◽  
Lak Cells ◽  
Mononuclear Leukocytes ◽  
Short Term ◽  
Lymphokine Activated Killer Cells ◽  
Primitive Neuroectodermal Tumors ◽  
Lak Cell ◽  
Neuroectodermal Tumors

✓ Short-term stimulation of nonantigen-primed peripheral blood mononuclear leukocytes with interleukin-2 generates a population of oncolytic effectors designated “lymphokine-activated killer” (LAK) cells. These LAK cells express potent lytic activity against a wide spectrum of fresh or cultured autochthonous (patient's own) and allogeneic (unrelated) tumors, yet specifically spare normal tissues. In this study, cells derived from primitive neuroectodermal tumors of the posterior fossa (PNET-PF) were examined for their sensitivity to LAK cytolysis utilizing an in vitro 4-hour chromium-51-release assay. Five early-passage cell lines, derived from primary PNET-PF, demonstrated significant sensitivity to LAK cell cytolysis. Lysis was equally effective in culture medium and cerebrospinal fluid. Three freshly excised PNET-PF exhibited similar susceptibility to lysis by autochthonous LAK cells. Greatly increased expansion of LAK cell cultures could be achieved by short-term stimulation with monoclonal anti-CD3 antibodies in addition to interleukin-2 activation. These findings constitute the preliminary in vitro foundations for potential intrathecal adoptive immunotherapy of PNET-PF with LAK cells.

scholarly journals Bone marrow transplantation with interleukin-2-activated bone marrow followed by interleukin-2 therapy for acute myeloid leukemia in mice

Blood ◽  
1990 ◽  
Vol 76 (11) ◽  
pp. 2187-2190 ◽  
Author(s):  
BS Charak ◽  
RK Brynes ◽  
S Groshen ◽  
SC Chen ◽  
A Mazumder
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Autologous Bone Marrow Transplantation ◽  
Interleukin 2 ◽  
Autologous Bone Marrow ◽  
Acute Myeloid

Abstract We have investigated approaches to induce graft-versus-leukemia (GVL) effect in autologous bone marrow transplantation (ABMT) without graft- versus-host disease to improve survival and cure in leukemia. The present study shows that bone marrow transplantation (BMT) using syngeneic bone marrow activated with interleukin-2 (ABM) for 24 hours in vitro, followed by interleukin-2 (IL-2) therapy, was superior to BMT with fresh, syngeneic bone marrow (FBM) in terms of survival and cure in mice with acute myeloid leukemia (P less than .001) and led to normal hematopoietic reconstitution. Addition of IL-2 therapy after BMT with FBM did not improve the results over BMT with FBM alone (P = .98). These results suggest that the GVL effect of ABMT can be enhanced by using ABM for BMT followed by IL-2 therapy without compromising engraftment.

scholarly journals Bone marrow transplantation with interleukin-2-activated bone marrow followed by interleukin-2 therapy for acute myeloid leukemia in mice

Blood ◽  
1990 ◽  
Vol 76 (11) ◽  
pp. 2187-2190 ◽  
Author(s):  
BS Charak ◽  
RK Brynes ◽  
S Groshen ◽  
SC Chen ◽  
A Mazumder
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Autologous Bone Marrow Transplantation ◽  
Interleukin 2 ◽  
Autologous Bone Marrow ◽  
Acute Myeloid

We have investigated approaches to induce graft-versus-leukemia (GVL) effect in autologous bone marrow transplantation (ABMT) without graft- versus-host disease to improve survival and cure in leukemia. The present study shows that bone marrow transplantation (BMT) using syngeneic bone marrow activated with interleukin-2 (ABM) for 24 hours in vitro, followed by interleukin-2 (IL-2) therapy, was superior to BMT with fresh, syngeneic bone marrow (FBM) in terms of survival and cure in mice with acute myeloid leukemia (P less than .001) and led to normal hematopoietic reconstitution. Addition of IL-2 therapy after BMT with FBM did not improve the results over BMT with FBM alone (P = .98). These results suggest that the GVL effect of ABMT can be enhanced by using ABM for BMT followed by IL-2 therapy without compromising engraftment.

Interleukin-2 and autologous lymphokine-activated killer cells in the treatment of malignant glioma

1986 ◽  
Vol 64 (5) ◽  
pp. 743-749 ◽  
Author(s):  
Steven K. Jacobs ◽  
Debra J. Wilson ◽  
Paul L. Kornblith ◽  
Elizabeth A. Grimm
Keyword(s):  
Malignant Glioma ◽  
Direct Injection ◽  
Interleukin 2 ◽  
Peripheral Blood Lymphocytes ◽  
Lak Cells ◽  
Lymphokine Activated Killer Cells ◽  
Content Type ◽  
Chromium Release ◽  
Neural Toxicity

✓ Nine patients with malignant glioma were treated with the lymphokine interleukin-2 (IL-2) or with lymphokine-activated killer (LAK) cells, and one patient received combination therapy with both LAK cells and IL-2. The LAK cells were generated by culturing recombinant IL-2 with peripheral blood lymphocytes obtained from brain-tumor patients. Escalating doses of LAK cells (108 to 1010) or IL-2 (104 to 106 U) were administered intraoperatively by direct injection into the brain tissue surrounding the cavity left by debulking the tumor. There were no signs of systemic or neural toxicity following treatment. The selective killing of the tumor by LAK cells used for these treatments was demonstrated by a chromium release microcytotoxicity assay which showed in vitro the ability of the LAK cells to lyse glioma cells but not normal cells.

scholarly journals An approach for the analysis of relapse and marrow reconstitution after autologous marrow transplantation using retrovirus-mediated gene transfer

Blood ◽  
1992 ◽  
Vol 79 (10) ◽  
pp. 2694-2700 ◽  
Author(s):  
DR Rill ◽  
RC Moen ◽  
M Buschle ◽  
C Bartholomew ◽  
NK Foreman ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Marrow Transplantation ◽  
Residual Disease ◽  
Marker Gene ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
Disease Recurrence ◽  
Malignant Cells

Abstract Autologous bone marrow transplantation (ABMT) is widely used as treatment for malignant disease. Although the major cause of treatment failure is relapse, it is unknown if this arises entirely because of residual disease in the patient or whether contaminating cells in the rescuing marrow contribute. Attempts to purge marrow of its putative residual malignant cells may delay hematopoietic reconstitution and are of uncertain efficacy. We now describe how retrovirus-mediated gene transfer may be used to elucidate the source of relapse after ABMT for acute myeloid leukemia and to evaluate the efficacy of purging. Clonogenic myeloid leukemic blast cells in patient marrow can be transduced with the NeoR gene-containing helper-free retrovirus, LNL6, with an efficacy of 0% to 23.5% (mean, 10.5%). Transduced colonies grow in selective media and the presence of the marker gene can be confirmed in individual malignant colonies by polymerase chain reaction. If such malignant cells remain in harvested “remission” marrow, they will therefore be marked after exposure to LNL6. Detection of the marker gene in the malignant cells present at any later relapse would be firm evidence that residual disease contributed to disease recurrence, and would permit rapid subsequent evaluation of purging techniques. The technique also marks normal marrow progenitors from patients with acute myeloblastic leukemia. These colony-forming cells can be detected in long-term marrow cultures at a frequency of 1% to 18% for up to 10 weeks after exposure to the vector. Animal models and analysis of probability tables both suggest that these levels of marking in vitro are sufficient to provide information about the mechanisms of relapse and the biology of marrow regeneration in vivo. These preclinical data form part of the basis for current clinical studies of gene transfer into marrow before ABMT.

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.

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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