[Monitoring Blood Markers to Predict Nivolumab Effectiveness in Esophageal Carcinoma].

We investigated whether monitoring the neutrophil-lymphocyte ratio(NLR)and serum interleukin 2 receptor-%lymphocyte ratio(sIL-2R/%Ly)could predict nivolumab(NIVO)effectiveness in treating 9 patients with esophageal cancer. The progression-free survival(PFS)was 292±44 days and overall survival(OS)was 456±136 days. One patient who had chemotherapy intolerance and switched to NIVO achieved CR, and the others had PD. Four patients had irAEs, which did not correlate with the treatment response. Patients with pretreatment low sIL-2R/%Ly and no NLR increase during treatment had significantly longer OS and better prognosis. Therefore, host parameters, such as NLR, sIL-2R, and lymphocyte counts, were significant in the real time monitoring of NIVO therapy for esophageal carcinoma.

Spinal cord sarcoidosis in Japan: utility of cerebrospinal fluid examination and nerve conduction study for diagnosis and prognosis prediction.

Spinal cord sarcoidosis (SCS) is rare, and its diagnosis is challenging. We examined clinical, laboratory, and imaging features in patients with SCS to obtain useful clues for diagnosis and prognosis. Eleven consecutive patients (four males, seven females) at a single Japanese institution were investigated. Median age at onset was 66 years old. The most frequent site affected, other than the nervous system, was the respiratory system. While histological confirmation of non-caseating granulomas was often found there, no patient had respiratory symptoms. Peripheral nerve involvement was detected in 64% of patients. Soluble IL-2 receptor (sIL-2R) levels in serum and cerebrospinal fluid (CSF) were elevated in 64% and 45% of patients, respectively, and this finding was more common than elevation of angiotensin-converting enzyme (ACE). 18F-fluorodeoxyglucose (FDG) positron emission tomography showed abnormally high uptake in spinal lesions of all examined patients. Although corticosteroids were administrated to all patients, and immuno-suppressants were prescribed to six (55%), the modified Rankin Scale was unchanged or worsened in four (36%) patients during the follow-up period. Neurological exacerbation of myelopathy was seen in four (36%) patients. Complete response rate was only seen in 9%. High levels of cell count, protein, ACE, and sIL-2R in CSF were significantly more frequent in patients with a marked improvement after immunotherapy than in the other patients. These results suggest that high serum and CSF sIL-2R, high uptake of FDG, and peripheral nerve involvement are indicative of SCS. Given that SCS is commonly intractable, CSF abnormalities may predict efficacy of immunotherapies.

Daclizumab en la esclerosis múltiple / Daclizumab in multiple sclerosis

Introducción. El daclizumab es un anticuerpo monoclonal dirigido contra la subunidad CD25 del receptor de la interleucina-2, investigado como terapia modificadora de la evolución de la enfermedad en la esclerosis múltiple. La presente revisión aborda cómo se desarrolló el fármaco, cuál es su mecanismo de acción conocido y los datos que se han obtenido hasta la fecha acerca de su eficacia y seguridad. Desarrollo. El daclizumab ha mostrado superioridad en prevención de brotes frente a placebo e interferón beta-1a de baja dosis en un nivel que lo sitúa a la par del resto de fármacos de primera línea actuales. El efecto sobre la progresión de la enfermedad y sobre parámetros de neurodegeneración, no obstante, no está aclarado. Por otro lado, presenta problemas de seguridad (riesgo de reacciones autoinmunes que incluyen hepatopatía fulminante y encefalitis) que han supuesto finalmente su retirada del mercado. El daclizumab introduce un nuevo mecanismo de acción a través del bloqueo de una interleucina clave en la regulación inmune y por su efecto sobre una población de células con capacidad reguladora, como son las células NK CD56 (bright). Conclusiones. El daclizumab ha demostrado eficacia para frenar el proceso inflamatorio de la esclerosis múltiple, aunque la aparición de efectos secundarios potencialmente graves no ha permitido que su uso impacte de manera significativa en la práctica clínica actual. El desarrollo de nuevos fármacos en la esclerosis múltiple debe estar supeditado a mantener o mejorar el perfil riesgo-beneficio respecto a los ya en uso

Introduction. Daclizumab is a monoclonal antibody directed against the CD25 subunit of the interleukin-2 receptor, investigated as a disease-modifying therapy in relapsing-remitting multiple sclerosis. The present review addresses how the drug was developed, the known mechanism of action of the drug and the up-to-date data of efficacy and safety. Development. Daclizumab has shown superiority in prevention of relapses against placebo and low-dose interferon beta-1a at a level that puts it on par with the rest of current first-line drugs. The effect on the progression of the disease and on neurodegeneration parameters, however, is not clear. On the other hand, it presents safety problems (mainly risk of autoimmunity phenomena including fulminant hepatopathy and encephalitis) that have supposed eventually its withdrawn from marketing. Daclizumab introduces a new mechanism of action through the blocking of a key interleukin in immune regulation and its effect on a population of cells with regulatory ability, such as the NK CD56(bright) cells. Conclusions. Daclizumab has shown efficacy in slowing the inflammatory process of multiple sclerosis, although the appearance of potentially serious side effects has not allowed its use to significantly impact current clinical practice. The development of new drugs in multiple sclerosis must be contingent on maintaining or improving the risk-benefit profile with respect to those already in use

Dosis repetidas de daclizumab para retrasar la instauración del inhibidor de la calcineurina en pacientes con trasplante cardiaco y disfunción renal postoperatoria / Repeated Daclizumab administration to delay the introduction of calcineurin inhibitors in heart transplant patients with postoperative renal dysfunction

El daclizumab es un antagonista del receptor de la IL-2 usado como terapia de inducción en el trasplante cardiaco con pocos efectos secundarios y baja tasa de infecciones. La insuficiencia renal postoperatoria tras un trasplante cardiaco es frecuente y potencialmente grave. La introducción de los inhibidores de la calcineurina en el postoperatorio puede agravar esta situación. Presentamos 6 casos de pacientes sometidos a trasplante cardiaco y que desarrollaron insuficiencia renal postoperatoria. En todos ellos se administró daclizumab de forma semanal para evitar la introducción del inhibidor de la calcineurina y permitir la recuperación renal. Una vez mejorada la función renal, se introdujo el inhibidor de la calcineurina. En todos los casos se recuperó la función renal y la tasa de complicaciones fue baja. La administración de dosis repetidas de daclizumab en pacientes con insuficiencia renal tras un trasplante cardiaco puede ser una alternativa para evitar el uso de inhibidores de la calcineurina y permitir así la recuperación de la función renal(AU)

Daclizumab is an interleukin-2 receptor antagonist which is used for induction therapy in heart transplant patients. It has few side effects and is associated with a low infection rate. Postoperative renal failure after heart transplantation is common and potentially fatal. The administration of calcineurin inhibitors in the postoperative period can aggravate the situation. We report the cases of six patients who underwent heart transplantation and developed acute renal failure in the immediate postoperative period. All were administered daclizumab weekly to avoid the introduction of calcineurin inhibitors and to facilitate recovery of renal function. Calcineurin inhibitors were introduced only once renal function had improved. Renal function recovered in all cases and there was a low complication rate. The administration of repeated doses of daclizumab to patients who experience acute postoperative renal failure after heart transplantation may provide an alternative therapeutic approach that enables calcineurin inhibitors to be avoided and, consequently, renal function to recover(AU)

Alemtuzumab induction and triple maintenance immunotherapy in kidney transplantation from donors after cardiac death.

We have used alemtuzumab in combination with triple maintenance immunosuppression in renal transplantation from donors after cardiac death between 2002 and 2006. We compared outcomes of induction therapy with alemtuzumab with interleukin-2 (IL-2) receptor antagonists (RA) and anti-lymphocyte antibodies. We used a retrospective sequential study design to examine 170 recipients of kidneys from donor after cardiac death (DCD) for survival, graft survival, time to first rejection, glomerular filtration and complications. Patients were stratified into high-risk and low-risk groups based on the following criteria: panel of reactive antibodies >20%, retransplants, Afro-American race. Induction with alemtuzumab was compared with anti-thymocyte globulin (ATG) in the high-risk and with IL-2RA in the low-risk group. Patients received triple immunosuppression with steroids, mycophenolate mofetil and calcineurin inhibitors. Patient survival, graft survival, rejection rate and glomerular filtration rate did not significantly differ between patients treated with alemtuzumab versus IL-2RAs or ATG. There was a trend towards reduced graft- and patient survival in the alemtuzumab group. There was an increased incidence of cytomegalovirus (CMV) infections in the alemtuzumab-induced group and a trend towards increased BK virus and bacterial infections. Induction of DCD kidney transplants with alemtuzumab compared to IL-2RA and ATG has no significant impact on acute rejection. It appears however that CMV infections are increased in patients induced with alemtuzumab. We therefore conclude that induction with alemtuzumab does not confer any advantage over traditional induction agents.

Respuesta estructurada a preguntas clínicas (CAT: Critical Appraisal Topics): en receptores con alto riego de desarrollar necrosis tubular aguda (NTA) post-trasplante. ¿Es útil la inducción con anticuerpos contra el receptor de la interleukina dos? / Are IL2 receptors antagonist useful in high risk acute tubular necrosis kidney recipients?

Se plantea si los receptores añosos de donantes añosos tienen más incidencia de NTA y si el uso de antagonistas del receptor de la IL2 contribuiría a disminuir la incidencia de función renal retrasada. Para responder a la primera cuestión se ha acudido a datos publicados de registros y a estudios uni o multicéntricos y se ha seleccionado el normograma de Irish que integra 16 variables clínicas del donante, receptor y trasplante, y se concluye que la edad del donante aumenta la probabilidad de desarrollar NTA. La segunda cuestión está respondida en la literatura en un meta-análisis que incluye 38 ensayos clínicos. De estos solamente 9 estudios (1.380 pacientes) registran la incidencia de función renal retrasada y están realizados contra placebo. En este subgrupo el riesgo relativo de padecer función renal retrasada en pacientes en los que se utilizan anticuerpos contra el receptor de la IL-2 vs placebo no alcanzó la significación estadística (0,87 IC95% 0,72 a 1,06). Por lo que de momento y hasta nuevos análisis podemos concluir que la utilización de antagonistas del receptor de la IL2 no tiene efecto protector para la aparición de NTA

The questions are if old recipients from old donor have more incidence of delayed graft function and if antagonists of Il-2 receptors use decreased the incidence of NTA post-transplant. To answer the first question we have come to information from registry and uni or multicenter studies. We have used the Irish normograme that included 16 clinical questions from donors, recipients and kidney transplant. We concluded that age of donors increases likelihood of delayed graft function. The second question is answered in the literature with information of a meta-analysis with 38 clinical studies. Of them 9 (1.380 patients) studied delayed graft function and are against placebo. The odds ratio for delayed graft function was 0.87(IC 95% 0,72 a 1,06). Therefore, at the moment, we can conclude that the utilization of antagonists of Il-2 receptors does not have protective effect to NTA

Evaluation of immunotherapy in the treatment of melanoma.

These data show that the extraordinary potency of the immune system can be harnessed to control or destroy melanoma. The proven impact has been limited for patients who have melanoma, but has been dramatic and lasting in selected groups. Recent improvements in understanding of immunology, including mechanisms regulating immune responses and methods of tumor cell escape, are already yielding improved clinical outcomes and potential avenues for extending benefits to more patients. Thus, although the full potential of this treatment modality has yet to be realized, the vanguard of the "treatment of tomorrow" has clearly arrived.

[Treatment of severe steroid-refractory graft-versus-host disease with IL-2R alpha chain (CD25) monoclonal antibody].

OBJECTIVE: To investigate the effects of IL-2R alpha chain (CD(25)) monoclonal antibody on severe steroid-refractory graft-versus-host disease (GVHD). METHODS: Seventeen patients (18 times) with severe steroid-refractory GVHD were treated with intravenous drip of humanized CD(25) monoclonal antibody on day 1, 3 or 4, 8, 15 and 22. The cumulative scoring of GVHD and status of infection were observed, and laboratory tests, including blood counting and blood biochemical test were made before and 1, 4, 8, 15, 22, 29, 36, 43 and 50 days after the treatment. RESULTS: (1) Eleven of the eighteen case-times (61.1%) got complete relief, five (27.8%) GVHD got partial relief, and two (11.1%) failed to get relief. (2) Seven case-times (33.3%) had infection. (3) Relapse of GVHD occurred in four of the eleven case-times with complete relief (36.4%). (4) No infusion-related reaction was observed. CONCLUSION: The monoclonal antibody against IL-2 receptor alpha chain (CD(25)) has a marked effect upon severe steroid-refractory GVHD.

Retroviral transduction of IL2RG into CD34(+) cells from X-linked severe combined immunodeficiency patients permits human T- and B-cell development in sheep chimeras.

X-linked severe combined immunodeficiency (XSCID) is caused by mutations of the common gamma chain of cytokine receptors, gamma(c). Because bone marrow transplantation (BMT) for XSCID does not provide complete immune reconstitution for many patients and because of the natural selective advantage conferred on lymphoid progenitors by the expression of normal gamma(c), XSCID is a good candidate disease for therapeutic retroviral gene transfer to hematopoietic stem cells. We studied XSCID patients who have persistent defects in B-cell and/or combined B- and T-cell function despite having received T cell-depleted haploidentical BMT. We compared transduction of autologous B-cell lines and granulocyte colony-stimulating factor-mobilized peripheral CD34(+) cells from these patients using an MFGS retrovirus vector containing the gamma(c) gene IL2RG pseudotyped with amphotropic, gibbon ape leukemia virus, or RD114 envelopes. Transduced B-cell lines and peripheral CD34(+) cells demonstrated provirus integration and new cell-surface gamma(c) expression. The chimeric sheep model was exploited to test development of XSCID CD34(+) cells into mature myeloid and lymphoid lineages. Transduced and untransduced XSCID CD34(+) cells injected into developing sheep fetuses gave rise to myeloid cells. However, only transduced gamma progenitors from XSCID patients developed into T and B cells. These results suggest that gene transfer to autologous peripheral CD34(+) cells using MFGS-gc retrovirus may benefit XSCID patients with persistent T- and B-cell deficits despite prior BMT.

Long-term care of pediatric renal transplant patients: from bench to bedside.

In this review, we discuss current and future issues in the management of pediatric renal transplant recipients, including the optimization of long-term graft function and the minimization of complications caused by immunosuppression. Long-term management involves not only the monitoring of graft function but also the identification of patients at risk for the development of complications. The identification of patients with immunoreactive or immunoregulatory responses can be performed molecular monitoring of the immune response. Also, the use of frequent surveillance kidney biopsies, surrogate markers of chronic rejection, and glomerular filtration rate will be a part of future management. Identifying high-risk patients enables the physician to optimize immunosuppression to limit acute rejection. Short-and long-term management of pediatric transplant patients also includes adequate monitoring of growth and the monitoring for post-transplant lymphoproliferative disease. Ongoing clinical trials are underway that focus on these novel approaches in caring for pediatric transplant recipients.

[Significance of soluble interleukin-2 receptor alpha chain in the management of patients with malignant lymphoma: a multi-center study].

A multi-center series of 117 patients with malignant lymphoma were analyzed to evaluate the clinical significance of soluble interleukin-2 receptor alpha chain (sIL-2R alpha). The initial levels of sIL-2R alpha ranged from 277 U/ml to 22,800 U/ml with a mean level of 3,451 +/- 4,268 U/ml and a median level of 1,600 U/ml. The sIL-2R alpha levels of the diffuse lymphoma/intermediate-grade subtypes defined by the LSG classification/Working Formulation were higher than those of the follicular lymphoma/low-grade subtypes. There was a tendency for B-cell lymphomas to show higher sIL-2R alpha levels than T-cell lymphomas. The sIL-2R alpha level was correlated with the Ann Arbor clinical stage (I, II versus III, IV), presence or absence of B symptoms, and performance status (0, 1 versus 2, 3, 4) of the patients. The sIL-2R alpha levels were in good accordance with the four risk groups defined by the International Prognostic Indices. Of 21 patients whose tumor burden was serially measured, the coefficients of correlation between sIL-2R alpha and tumor mass were > 0.6 in 18 cases. Sixty-two patients achieved complete remission (CR) during the study; the initial and minimum sIL-2R alpha levels were lower than those of the non-CR patients. This study confirmed that sIL-2R alpha is a convenient and useful marker in the management of malignant lymphoma.

IL-2Ralpha-Directed monoclonal antibodies provide effective therapy in a murine model of adult T-cell leukemia by a mechanism other than blockade of IL-2/IL-2Ralpha interaction.

Adult T-cell leukemia (ATL) develops in a small proportion of human T-cell lymphotrophic virus-I infected individuals. The leukemia consists of an overabundance of activated T cells, which are characterized by the expression of CD25, or IL-2Ralpha, on their cell surface. Presently, there is not an accepted curative therapy for ATL. We developed an in vivo model of ATL in non-obese diabetic/severe combined immunodeficient (NOD/ SCID) mice by introducing cells from an ATL patient (MET-1) into the mice. The leukemic cells proliferated in these mice that lack functional T, B, and natural killer (NK) cells. The MET-1 leukemic cells could be monitored by measurements of both serum soluble Tac (IL-2Ralpha) and soluble human beta2-microglobulin (beta2mu) by ELISA. The disease progressed to death in the mice after approximately 4-6 weeks. The mice developed grossly enlarged spleens and a leukemia involving ATL cells that retained the phenotype and the T-cell receptor rearrangement and human T-cell lymphotrophic virus-I integration pattern of the patient's ATL leukemia cells. This model is of value for testing the efficacy of novel therapeutic agents for ATL. The administration of humanized anti-Tac (HAT), murine anti-Tac (MAT), and 7G7/B6, all of which target IL-2Ralpha, significantly delayed the progression of the leukemia and prolonged the survival of the tumor-bearing mice. In particular, HAT induced complete remissions in 4 of 19 mice and partial remissions in the remainder. It appears that the antibodies act by a mechanism that had not been anticipated. The prevailing view is that antibodies to the IL-2Ralpha receptor have their effective action by blocking the interaction of IL-2 with its growth factor receptor, thereby inducing cytokine deprivation apoptosis. However, although both HAT and MAT block the binding of IL-2 to IL-2Ralpha of the high affinity receptor, the 7G7/B6 monoclonal antibody binds to a different epitope on the IL-2Ralpha receptor, one that is not involved in IL-2 binding. This suggested that the antibodies provide an effective therapy by a mechanism other than induction of cytokine deprivation. In accord with this view, the MET-1 cells obtained from the spleens of leukemic mice did not produce IL-2, nor did they express IL-2 mRNA as assessed by reverse transcription-PCR. Another possible conventional mechanism of action involves complement-mediated killing. However, although MAT and 7G7/B6 fix rabbit complement, HAT does not do so. Furthermore, in the presence of NOD/SCID mouse serum, there was no complement-mediated lysis of MET-1 cells. In addition, the antibodies did not manifest antibody-dependent cellular cytotoxicity with NOD/SCID splenocytes that virtually lack NK cells as the effector cells as assessed in an in vitro chromium-release assay. However, in contrast to the efficacy of intact HAT, the F(ab')2 version of this antibody was not effective in prolonging the survival of mice injected with MET-1 ATL cells. In conclusion, in our murine model of ATL, monoclonal antibodies, HAT, MAT, and 7G7/B6, appear to delay progression of the leukemia by a mechanism of action that is different from the accepted mechanism of IL-2 deprivation leading to cell death. We consider two alternatives: the first, antibody-dependent cellular cytotoxicity mediated by FcRI- or FcRIII-expressing cells other than NK cells, such as monocytes or polymorphonuclear leukocytes. The second alternative we consider involves direct induction of apoptosis by the anti-IL-2R antibodies in vivo. It has been shown that the IL-2R is a critical element in the peripheral self-tolerance T-cell suicide mechanism involved in the phenomenon of activation-induced cell death.

Radioimmunotherapy of interleukin-2R - expressing adult T-cell leukemia with yttrium-90-labeled anti-tac

Adult T-cell leukemia (ATL) is a malignancy of mature lumphocytes caused by the retrovirus human T-cell lymphotropic virus-I. It is an aggressive leukemia with a median survival time of 9 months: no chemotherapy regimen appears successful inducing long-term disease-free survival. The scientific basis of the present study is the ATL cells express high-affinity interleukin-2 receptors identified by the anti-Tac monoclonal antibody, whereas normal resting cells do not. To exploit this differnce, we administered anti-Tac armed with Yttrium-90 (Y) to 18 patients with ATL initially (first 9 patients) in a phase I dose-escalation trial and subsequently (second group of 9 patients) in a phase II trial involving a uniform 10-mCi dose of Y-labeled anti-Tac. Patients undergoing a remission were permitted to receive up to eight additional doses. At the 5-to 15-mCi doses used, 9 of 16 evaluable patients responded to Y anti-Tac with a partial (7 patients) or complete (2 patients) remission. The responses observed represent improved efficacy in terms of length of remission when compared with previous results with unmodified anti-Tac. Clinically meaningful (> grade 3) toxicity was largely limited to the hematopoietic system. In conclusion, radioimmunotherapy with Y anti-Tac directed toward the IL-2R expressed on ATL cells may provide a useful approach for treatment of this aggressive malignancy.(AU)