Combination therapy of anti-CD4 and anti-IL6 monoclonal antibodies in a case of severe spondylarthropathy.
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Antibodies, Monoclonal↗
Biomedical subjects
E Racadot
Publications and source records attributed to E Racadot.
Comparative preclinical study of three bone marrow purging methods using PCR evaluation of residual t(14;18) lymphoma cells.
The t(14;18) chromosomal translocation occurring in most follicular lymphomas can be exploited by a Bcl2/JH polymerase chain reaction (PCR) to detect residual disease and to monitor the effectiveness of ex-vivo tumor cell immunological purging. We first demonstrated the 10(-5) Bcl2/JH PCR sensitivity with serial dilutions of OCY-LY8 lymphoma cell lines in normal mononuclear cells; and then the specificity and reproductibility of this technique by analysing follicular and non follicular lymphoma samples. With the Bcl2/JH PCR, we tested the efficiency of three marrow purging protocols with an experimentally contaminated bone marrow either treated by three anti-B cell monoclonal antibodies (mAb) followed by three rounds of rabbit complement or two rounds of immunomagnetics beads. Samples obtained after each purging were amplified by Bcl2/JH PCR and hybridized with PFL3 probe. We were able to produce a 2 to 3 log tumor cell reduction after three rounds of complement and a 4 to 5 log reduction after two rounds of beads. This study showed that it is feasible to use the Bcl2/JH PCR technique for residual cell lymphoma detection in patients undergoing intensive chemotherapy or BM transplantation. These results indicate that ex-vivo immunomagnetic BM purging is probably superior to complement mediated lysis for the eradication of B lymphoma cells from the marrow of patients undergoing autologous transplantation.
Animals↗
Successful cord blood stem cell transplantation for congenital erythropoietic porphyria (Gunther's disease).
Congenital erythropoietic porphyria (Gunther's disease, GD) is a rare autosomal recessive disease. It results from the deficiency of uroporphyrinogen III synthase, the fourth enzyme on the metabolic pathway of heme synthesis. GD leads to severe scarring of the face and hands as a result of photosensitivity and fragility of the skin due to uroporphyrin I and coproporphyrin I accumulation. It also causes erythrocyte fragility leading to haemolytic anaemia. The other clinical features include hirsutism, red discolouration of teeth, finger-nails and urine and stunted growth. The outcome is poor, and the disfiguring nature of GD may partly explain the legend of the werewolf. No curative treatment was known until 1991, when the first case of BMT in GD was reported. The clinical and biological outcome after transplantation was encouraging, with an important regression of the symptoms of the disease, but the child died of CMV-infection 11 months after BMT. We report the second case of GD treated successfully by stem cell transplantation using umbilical cord blood from an HLA-identical brother in a 4-year-old girl suffering from severe GD. Our patient is very well 10 months after transplantation. We confirm that stem cell transplantation is curative for GD.
Amniocentesis↗
Biological assessment and MRI monitoring of the therapeutic efficacy of a monoclonal anti-T CD4 antibody in multiple sclerosis patients.
An initial group of 21 patients plus a second group of 14 patients with active multiple sclerosis (MS) (18 progressive and 17 relapsing-remitting forms) were treated with a murine monoclonal anti-T CD4/BF5 antibody as part of a phase I open trial. Tolerance was relatively good: minor general side-effects occurred in 22 patients only upon the first mAb infusion. One year later, functional disability was stabilised in only six of the 35 patients and after 2 years in two patients only (among 21). One year after treatment, nine of the 17 relapsing-remitting patients were relapse-free. CD4 counts decreased dramatically 2 h after treatment. These counts were back to baseline counts at 3 months. A transient increase was found in IL-6 and TNF alpha levels 2 h after treatment, which probably accounts for the observed side effects. Cell adhesion molecule levels were not modified. Serial MRI scans were performed in the second group of 14 patients. In all of these patients, lesion modifications were observed in the three scans performed prior to treatment. Yet, no changes in the lesions were noted on the MRI scans performed over the following 3 months. These findings demonstrate the feasibility of this treatment insofar as it induced a marked CD4 lymphocyte depletion. However, it did not seem to stabilise the evolution of the disease--although one must be careful in drawing such conclusions in a phase I trial--or to curb the evolution of MRI-documented lesions.
Antibodies, Monoclonal↗
Pilot clinical trial of an anti-TNF alpha monoclonal antibody for the treatment of septic shock.
OBJECTIVE: To determine the safety and pharmacokinetics of an anti-tumour necrosis factor (TNF alpha) monoclonal antibody in the treatment of septic shock, and to evaluate the biological evolution of cytokine response. DESIGN: Open-label, prospective, pilot trial with escalating doses of a murine monoclonal antibody (B-C7) directed against TNF alpha. SETTING: University medical centre intensive care unit. PATIENTS: Nine patients with septic shock, who received standard supportive care and antimicrobial therapy in addition to the anti-TNF alpha antibody. INTERVENTIONS: Patients were treated intravenously with one of three escalating doses of B-C7 monoclonal antibody (MoAb): 0.4 mg/kg, 0.8 mg/kg, 1 mg/kg. RESULTS: MoAb was well tolerated despite the development of human anti-mouse antibodies (HAMA) for each patient; B-C7 plasma levels were dose-dependent. At study entry, TNF alpha and IL-6 levels were detected in six and seven patients respectively; IL-1 levels were low and interferon-gamma was undetectable. CONCLUSIONS: No side effects were noted during treatment regardless of the dose used; however, further studies are needed to determine the clinical efficacy of this agent in septic shock.
APACHE↗
Outcome of lymphocyte subsets and cytokines during combined CD4/anti-IL-2R monoclonal antibody therapy in kidney transplantation.
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Antibodies, Monoclonal↗
Sequential use of three monoclonal antibodies in corticosteroid-resistant acute GVHD: a multicentric pilot study including 15 patients.
We previously demonstrated the potential of anti-IL-2R and anti-TNF alpha moAbs in the treatment of acute graft-versus-host disease (GVHD). However, one major problem was the recurrence of acute GVHD on treatment discontinuation. To target the two main effectors of acute GVHD lesions, T and NK cells on the one hand and TNF alpha on the other, we combined anti-CD2 and anti-TNF alpha moAbs. Then to prevent acute GVHD recurrence, we administered anti-IL-2R moAbs known for their inhibitory effect on activated cells. We included 15 patients with steroid-resistant acute GVHD. Seven were grafted from a genotypically-identical sibling, 5 from HLA-matched unrelated donors and 3 from partially-matched related donor. Prophylaxis of acute GVHD consisted of cyclosporin A +/- methotrexate or corticosteroids. Before treatment 6 patients had grade II, 2 patients grade III and 7 patients grade IV acute GVHD. Anti-TNF alpha (B-C7) moAbs (10 mg/day/4 days) were combined with anti-CD2 (B-E2) moAbs (10 mg/day/10 days) on the fifth day (day 5), anti-IL-2 receptor (B-B10) moAbs were given at 10 mg/day/10 days followed by 5 mg every other day for another 50 days. On day 15, 5 patients achieved a complete remission, 4 a very good partial response (62% a good response), 2 had a partial response and 4 did not respond. GVHD recurred in 4 of the 9 responders, although anti-IL-2R moAb treatment was maintained. Three patients are long-term survivors without chronic GVHD.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Disease↗
CD4 and CD25 monoclonal antibody cocktail in kidney transplant rejection prophylaxis: clinical results of a pilot study.
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Adrenal Cortex Hormones↗
Herpes virus-related lymphoproliferative disorders following allogeneic bone marrow transplantation: clinical and biological characteristics of six cases.
The present paper describes six cases of lymphoproliferative disorders (LPD) occurring after bone marrow transplantation. Treatments were ineffective and disease was rapidly fatal in all patients, although immunotyping of cells in blood, bone marrow or cerebrospinal fluid was helpful to establish the diagnosis of LPD. Monoclonality was demonstrated in the 4 cases which it was possible to analyse. Herpes virus genome was present in tumoral cells of 4 in 4 cases tested for EBV, one in 3 cases tested for CMV, one in 3 cases tested for HHV6 and 3 in 3 cases tested for HSV. Patients developing LPD should benefit from earlier diagnosis and new therapeutic approaches such as donor lymphocyte infusions, while further studies are necessary to elucidate the role of Herpes viruses in the pathogenesis of LPD.
Adolescent↗
Clinical and immunological follow-up of patients with AIDS-associated Kaposi's sarcoma treated with an anti-IL-6 monoclonal antibody.
Ten AIDS patients with Kaposi's sarcoma (four in stage II A, four in stage III A, one in stage III B and one in stage IV of the disease) were treated for 14 days with B-E8, an anti-IL-6 monoclonal antibody (IgG1), at a daily dose of 10 mg. No side-effects were observed, but no patients experienced a complete or partial response. No modification was noted in the analysis of lymphocyte subsets, except for a transient decline in the number of cells expressing CD56, accompanied by altered NK activity in four of the seven evaluable patients. Anti-IL-6 mAb prevented the binding of IL-6 to its cell membrane receptor, as documented by the decline in C reactive protein levels. However, anti-IL-6 mAb induced the circulation of significant amounts of IL-6, probably in the form of monomeric immune complexes. The sera, analysed on B9 cell line, demonstrated a stimulating activity, indicating that hypersensitive cells were able to cleave these complexes. This observation, together with the clinical inefficacy of the treatment, should prompt us to be careful with the use of unmanipulated single monoclonal antibodies, especially in cancer patients.
Acquired Immunodeficiency Syndrome↗
Immunophenotype of adult acute lymphoblastic leukemia, clinical parameters, and outcome: an analysis of a prospective trial including 562 tested patients (LALA87). French Group on Therapy for Adult Acute Lymphoblastic Leukemia.
The aim of the multicentric trial LALA87 was to test the efficacy of different postremission therapies in adults (15 to 60 year olds) with acute lymphoblastic leukemia (ALL). An immunologic subclassification based on surface marker expression was proposed. Among the 562 tested patients, 511 were assigned either to the B lineage (361 cases, 63%) or to the T lineage (150 cases, 26%). T-ALL were significantly associated with male sex, age less than 35 years, mediastinal mass, central nervous system involvement, high white blood cell count, and low anemia. In a univariate and multivariate analysis, T-cell leukemia had a more favorable outcome than B-cell leukemia with respective median disease-free survivals (DFSs) of 28 and 14 months (P < .005). However, the type of postremission therapy modifies the value of the immunophenotype prognostic factor. In the chemotherapy arm, T-ALL patients (26 patients) had a more favorable outcome than B-ALL patients (57 patients) (P < .003). In the autologous bone marrow transplantation (ABMT) arm, the apparent better outcome of T-ALL patients (35 T/50 B) did not reach statistical significance (P = .2) and there was no difference in the allogeneic bone marrow transplantation (alloBMT) arm (37 T/71 B: P = .9). In the B-cell-lineage leukemias, subclassification by stages and myeloid antigen coexpression (10%) were not associated with different prognosis. CD10+ T-ALL (31 patients) were associated with a better DFS compared with the CD10- T-ALL (73 patients) with respective median DFS, not reached and 18.5 months (P = .04).
Adult↗
Interleukin-6 antibodies in rheumatoid arthritis.
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Antibodies, Monoclonal↗
Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. French Group of Therapy of Adult Acute Lymphoblastic Leukemia.
PURPOSE: Optimal postremission therapy remains controversial in adult patients with acute lymphoblastic leukemia (ALL). In a large multicentric trial (LALA87), we compared allogeneic bone marrow transplantation (BMT) with other postremission therapies (chemotherapy or autologous transplantation) using the result of the human leukocyte antigen (HLA) typing as a random allocation. PATIENTS AND METHODS: Patient eligibility requirements were as follows: (1) inclusion in LALA87 trial, (2) complete response to induction or salvage therapy, (3) age 15 to 40 years, and (4) at least one potential sibling donor. Patients with an HLA-identical sibling were assigned to the BMT group, while patients without a sibling donor constituted the control group. Allogeneic transplantation was scheduled for patients in the BMT group; in the control group, patients were randomly allocated to receive chemotherapy or autologous transplantation. RESULTS: Of 284 eligible points, 257 entered the study: 116 were allocated to the BMT group and 141 to the control group. The 5-year survival rates were not statistically significantly different between the two groups. When only patients with high-risk ALL were considered (those with [1] Philadelphia chromosome [Ph1] ALL, [2] null or undifferentiated ALL, or [3] c-ALL with either age greater than 35 years or WBC count > 30 x 10(9)/L or time to achieve complete remission > 4 weeks), overall survival (P = .03) and disease-free-survival (P = .01) were better for the BMT group compared with the control group (5-year overall survival rates, 44% v 20%; 5-year disease-free survival rates, 39% v 14%). CONCLUSION: Allogeneic transplantation does not improve survival in patients with standard-risk ALL and should be recommended only for patients with adverse prognostic factors.
Adolescent↗
Autologous BMT for post-remission therapy in adult ALL: an immunological approach. For The French Group of Therapy of Adult ALL.
Among patients included in the multicentric trial ALL87, 95 patients were randomly allocated to purged ABMT arm for post-remission therapy. Immunological phenotyping performed in patients at diagnosis allowed to assigned 51 patients (54%) to the B lineage and 34 patients (36%) to the T lineage. Only 64 patients (67%) actually received ABMT mainly because of early relapses. Fifty-two patients were depleted according to the protocol: 25 B-ALL were depleted with CD10+CD19 mAbs, 19 T-ALL with CD2+CD5+CD7 mAbs and 8 patients received an Asta-Z purged BMT. Among the 12 remaining patients, 4 received Asta-Z purged BMT and 8 an unpurged one. Using an intention to treat analysis, overall survival and event free survival were similar to results observed in chemotherapy group. This study emphasizes the importance of a precise phenotyping at ALL diagnosis which allows specific immunologic bone marrow purging for ABMT.
Adolescent↗
[Leukocyte expression of the LFA-1 adhesion molecule in spondylarthropathies].
The expression of adhesion molecule Leukocyte Function Antigen-1 (LFA-1) on peripheral blood leukocytes was evaluated (using a monoclonal antibody anti CD11a/LFA-1) in 52 spondylarthropathies (SA) (35 HLA B27 positive), 12 healthy patients, 24 active rheumatoid arthritis (RA) and 12 systemic lupus (SLE) patients. LFA-1 expression on lymphocytes was similar in the different groups of patients, but LFA-1 expression on granulocytes was higher in SA than in controls (p < 0.05) or in RA or SLE. Fluorescence intensity of anti LFA-1 staining on SA granulocytes correlated with serum IgA levels. There was no difference between HLA B27 positive/negative, biologically inflammatory (CRP > 21 mg/l)/non inflammatory SA patients. This study seems to confirm the granulocyte and IgA involvement in immunopathogenesis of spondylarthropathies.
Adolescent↗
Treatment of steroid-resistant acute graft-versus-host disease with an anti-IL-2-receptor monoclonal antibody (BT 563) in children who received T cell-depleted, partially matched, related bone marrow transplants.
Fifteen children with steroid-resistant acute graft-versus-host disease (GVHD, grade II-IV) were treated with a murine monoclonal antibody (BT 563) specific for the alpha subunit of the interleukin-2 receptor (IL-2R). All had inherited diseases of the bone marrow and had received T cell-depleted marrow from a partially matched related donor. BT 563 antibody was given at a daily dose of 0.2 mg/kg. Treatment was continued until GVHD was controlled and the methylprednisolone administration was tapered to < or = 2 mg/kg/day. No side-effects were noted. Eleven of the 15 patients reached complete remission and a partial remission occurred in two. This good response rate was associated with early treatment (mean time after GVHD onset 7.7 +/- 5.3 days) and prolonged treatment (mean 25.9 +/- 10.6 days) compared with previously published data on BT 563 antibody usage. Relapses occurred in six of the 13 responders but a further remission was induced by the same treatment. Chronic GVHD developed in six cases and one of them died of GVHD-associated infection. Ten of the 15 patients are long-term survivors and are free of chronic GVHD. The results of this pilot study indicate that early and lengthy treatment with anti-IL-2R monoclonal antibody is both safe and effective against steroid-resistant GVHD in young children and indicate that further trials of anti-IL-2R antibody as first-line therapy of acute GVHD are warranted.
Acute Disease↗
Variability of the alloreactive T-cell response to human leukemic blasts.
Clinical and experimental data suggest a role for the immune response in preventing leukemic relapses after allogeneic bone marrow transplantation (BMT): the graft-versus-leukemia (GVL) effect. In this report, we have evaluated the response of normal donor lymphocytes against allogeneic leukemic cells as an in vitro model of the GVL effect. We used a limiting dilution technique in order to determine the frequency of cytotoxic T-lymphocyte precursors (pre-CTL) against allogeneic leukemic blasts among normal donor lymphocytes. We demonstrate a considerable variability of CTL precursor frequency. This variability depended on leukemic populations since, for a given leukemia, the pre-CTL frequency was comparable among our tested normal allogeneic donors. Moreover, when HLA-DR negative leukemias were used as allostimulators, the pre-CTL frequencies were extremely low. In order to verify the impact of leukemic DR expression on the stimulatory capacity of leukemic cells, we selected and analyzed in mixed lymphocyte tumor cell culture (MLTC), a panel of myelogenous and lymphoblastic leukemias with variable levels of DR expression, each against different allogeneic responders. Our results demonstrated a close correlation (r = 0.953, p < 0.0001) between the proliferative response of alloactivated lymphocytes and the percentage of stimulatory leukemic cells expressing HLA-DR molecules. Anti-MHC class II monoclonal antibodies inhibited the lymphocyte proliferation in the MLTC, confirming the preponderant role of DR in the generation of this response. Overall, our results demonstrate the extreme variability of leukemic cells in their allostimulatory capacity and the central role of DR expression in determining leukemic allo-recognition. In the setting of a clinical protocol, our data suggest that the infusion of allogeneic T lymphocytes in a DR negative leukemia will not lead to an alloreactive T-cell anti-tumor effect.
HLA-DR Antigens↗
Interleukin-1 administration before lethal irradiation and allogeneic bone marrow transplantation: early transient increase of peripheral granulocytes and successful engraftment with accelerated leukocyte, erythrocyte, and platelet recovery.
Administration of interleukin-1 beta (IL-1 beta) before a lethal irradiation with or without allogeneic bone marrow transplantation (BMT) protects greater than 90% of the irradiated mice. To approach the mechanisms responsible for the radioprotective effect of IL-1, we examined the effects of IL-1 pretreatment on engraftment and kinetics of peripheral blood, spleen, and marrow cell reconstitution after irradiation and BMT. Although the BMT was not necessary for the survival of the IL-1-pretreated lethally irradiated mice, allogeneic marrow did engraft in these mice as evaluated in the spleen and marrow 2 months after BMT. IL-1 pretreatment significantly accelerated hematopoietic recovery versus transplanted saline-treated controls with a pronounced enhancement of peripheral leukocyte, platelet, and erythrocyte recovery. Leukocyte recovery in IL-1-pretreated mice was unique in that IL-1 first induced an early transient (maximum at day 7) increase of peripheral granulocytes before accelerating leukocyte recovery after day 11. IL-1 pretreatment also significantly enhanced marrow cell recovery after allogeneic BMT with an eightfold increase in marrow cellularity from day 4 to 11 versus control transplanted mice. When lethal irradiation was not followed by allogeneic BMT. IL-1 pretreatment also affected the peripheral reconstitution of leukocytes, platelets, and erythrocytes. Interestingly, in the absence of BMT, IL-1 also induced an early circulation of peripheral granulocytes. Overall, our data demonstrate that a single administration of IL-1 before lethal irradiation and allogeneic BMT can induce an early transient increase of circulating granulocytes, followed by an accelerated multilineage recovery and long-term allogeneic engraftment.
Animals↗