RESUMEN
BACKGROUND: Several commercial and academic autologous chimeric antigen receptor T-cell (CAR-T) products targeting CD19 have been approved in Europe for relapsed/refractory B-cell acute lymphoblastic leukemia, high-grade B-cell lymphoma and mantle cell lymphoma. Products for other diseases such as multiple myeloma and follicular lymphoma are likely to be approved by the European Medicines Agency in the near future. DESIGN: The European Society for Blood and Marrow Transplantation (EBMT)-Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association collaborated to draft best practice recommendations based on the current literature to support health care professionals in delivering consistent, high-quality care in this rapidly moving field. RESULTS: Thirty-six CAR-T experts (medical, nursing, pharmacy/laboratory) assembled to draft recommendations to cover all aspects of CAR-T patient care and supply chain management, from patient selection to long-term follow-up, post-authorisation safety surveillance and regulatory issues. CONCLUSIONS: We provide practical, clinically relevant recommendations on the use of these high-cost, logistically complex therapies for haematologists/oncologists, nurses and other stakeholders including pharmacists and health sector administrators involved in the delivery of CAR-T in the clinic.
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Hematología , Receptores Quiméricos de Antígenos , Acreditación , Adulto , Médula Ósea , Humanos , Inmunoterapia Adoptiva , Receptores de Antígenos de Linfocitos TRESUMEN
The specific niche adaptations that facilitate primary disease and Acute Lymphoblastic Leukaemia (ALL) survival after induction chemotherapy remain unclear. Here, we show that Bone Marrow (BM) adipocytes dynamically evolve during ALL pathogenesis and therapy, transitioning from cellular depletion in the primary leukaemia niche to a fully reconstituted state upon remission induction. Functionally, adipocyte niches elicit a fate switch in ALL cells towards slow-proliferation and cellular quiescence, highlighting the critical contribution of the adipocyte dynamic to disease establishment and chemotherapy resistance. Mechanistically, adipocyte niche interaction targets posttranscriptional networks and suppresses protein biosynthesis in ALL cells. Treatment with general control nonderepressible 2 inhibitor (GCN2ib) alleviates adipocyte-mediated translational repression and rescues ALL cell quiescence thereby significantly reducing the cytoprotective effect of adipocytes against chemotherapy and other extrinsic stressors. These data establish how adipocyte driven restrictions of the ALL proteome benefit ALL tumours, preventing their elimination, and suggest ways to manipulate adipocyte-mediated ALL resistance.
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Adipocitos/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Células 3T3-L1 , Adulto , Animales , Biopsia , Médula Ósea/patología , Linaje de la Célula , Supervivencia Celular , Humanos , Ratones , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Proteoma/metabolismo , Estrés Fisiológico , Análisis de Supervivencia , Adulto JovenRESUMEN
ADMIRE was a multicenter, randomized-controlled, open, phase IIB superiority trial in previously untreated chronic lymphocytic leukemia. Conventional front-line therapy in fit patients is fludarabine, cyclophosphamide and rituximab (FCR). Initial evidence from non-randomized phase II trials suggested that the addition of mitoxantrone to FCR (FCM-R) improved remission rates. Two hundred and fifteen patients were recruited to assess the primary end point of complete remission (CR) rates according to International Workshop on Chronic Lymphocytic Leukemia criteria. Secondary end points were progression-free survival (PFS), overall survival (OS), overall response rate, minimal residual disease (MRD) negativity and safety. At final analysis, CR rates were 69.8 FCR vs 69.3% FCM-R (adjusted odds ratio (OR): 0.97; 95% confidence interval (CI): (0.53-1.79), P=0.932). MRD-negativity rates were 59.3 FCR vs 50.5% FCM-R (adjusted OR: 0.70; 95% CI: (0.39-1.26), P=0.231). During treatment, 60.0% (n=129) of participants received granulocyte colony-stimulating factor as secondary prophylaxis for neutropenia, a lower proportion on FCR compared with FCM-R (56.1 vs 63.9%). The toxicity of both regimens was acceptable. There are no significant differences between the treatment groups for PFS and OS. The trial demonstrated that the addition of mitoxantrone to FCR did not increase the depth of response. Oral FCR was well tolerated and resulted in impressive responses in terms of CR rates and MRD negativity compared with historical series with intravenous chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Adulto , Anciano , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Neoplasia Residual , Neutropenia/tratamiento farmacológico , Neutropenia/prevención & control , Inducción de Remisión , Rituximab/administración & dosificación , Tasa de Supervivencia , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/análogos & derivadosAsunto(s)
Variaciones en el Número de Copia de ADN , Leucemia Linfocítica Crónica de Células B/genética , Rituximab/uso terapéutico , Proteína p53 Supresora de Tumor/genética , Células Clonales/efectos de los fármacos , Células Clonales/patología , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/patología , Mutación , Rituximab/farmacología , Resultado del TratamientoRESUMEN
Compounds targeting phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling are being investigated in multiple clinical settings, but drug resistance may reduce their benefit. Compound rechallenge after drug holidays can overcome such resistance, yet little is known about the impact of drug holidays on cell biochemistry. We found that PI3K inhibitor (PI3Ki)-resistant cells cultured in the absence of PI3Ki developed a proliferative defect, increased oxygen consumption and accumulated reactive oxygen species (ROS), leading to lactate production through hypoxia-inducible factor-1α. This metabolic imbalance was reversed by mammalian target of rapamycin complex 1 (mTORC1) inhibitors. Interestingly, neither AKT nor c-MYC was involved in mediating the metabolic phenotype, despite the latter contributing to resistant cells' proliferation. These data suggest that an AKT-independent PI3K/mTORC1 axis operates in these cells. The excessive ROS hampered cell division, and the metabolic phenotype made resistant cells more sensitive to hydrogen peroxide and nutrient starvation. Thus, the proliferative defect of PI3Ki-resistant cells during drug holidays is caused by defective metabolic adaptation to chronic PI3K/mTOR pathway inhibition. This metabolic imbalance may open the therapeutic window for challenge with metabolic drugs during drug holidays.
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Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Inhibidores Enzimáticos/administración & dosificación , Inhibidores de las Quinasa Fosfoinosítidos-3 , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Humanos , Células MCF-7 , Diana Mecanicista del Complejo 1 de la Rapamicina , Complejos Multiproteicos/antagonistas & inhibidores , Complejos Multiproteicos/genética , Estrés Oxidativo/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/genéticaRESUMEN
Efficacy of lenalidomide was investigated in 103 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) treated on the prospective, multicenter randomized phase-II CLL-009 trial. Interphase cytogenetic and mutational analyses identified TP53 mutations, unmutated IGHV, or del(17p) in 36/96 (37.5%), 68/88 (77.3%) or 22/92 (23.9%) patients. The overall response rate (ORR) was 40.4% (42/104). ORRs were similar irrespective of TP53 mutation (36.1% (13/36) vs 43.3% (26/60) for patients with vs without mutation) or IGHV mutation status (45.0% (9/20) vs 39.1% (27/68)); however, patients with del(17p) had lower ORRs than those without del(17p) (21.7% (5/22) vs 47.1% (33/70); P=0.049). No significant differences in progression-free survival and overall survival (OS) were observed when comparing subgroups defined by the presence or absence of high-risk genetic characteristics. In multivariate analyses, only multiple prior therapies (⩾3 lines) significantly impacted outcomes (median OS: 21.2 months vs not reached; P=0.019). This analysis indicates that lenalidomide is active in patients with relapsed/refractory CLL with unfavorable genetic profiles, including TP53 inactivation or unmutated IGHV. (ClinicalTrials.gov identifier: NCT00963105).
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Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos , Factores Inmunológicos/uso terapéutico , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Talidomida/análogos & derivados , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Lenalidomida , Leucemia Linfocítica Crónica de Células B/genética , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Recurrencia , Retratamiento , Análisis de Supervivencia , Talidomida/uso terapéutico , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Chronic lymphocytic leukemia (CLL) is characterized by apoptosis resistance and a dysfunctional immune system. Previous reports suggested a potential role of myeloid cells in mediating these defects. However, the composition and function of CLL-associated myeloid cells have not been thoroughly investigated in vivo. Using the Eµ-TCL1 mouse model, we observed severe skewing of myeloid cell populations with CLL development. Monocytes and M2-like macrophages infiltrated the peritoneal cavity of leukemic mice. Monocytes also accumulated in the spleen in a CCR2-dependent manner, and were severely skewed toward Ly6C(low) patrolling or nonclassical phenotype. In addition, the percentage of MHC-II(hi) dendritic cells and macrophages significantly dropped in the spleen. Gene expression profiling of CLL-associated monocytes revealed aberrantly high PD-L1 expression and secretion of multiple inflammatory and immunosuppressive cytokines like interleukin-10, tumor necrosis factor-α and CXCL9. In vivo myeloid cell depletion using liposomal Clodronate resulted in a significant control of CLL development accompanied by a pronounced repair of innate immune cell phenotypes and a partial resolution of systemic inflammation. In addition, CLL-associated skewing of T cells toward antigen-experienced phenotypes was repaired. The presented data suggest that targeting nonmalignant myeloid cells might serve as a novel immunotherapeutical strategy for CLL.
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Ácido Clodrónico/farmacología , Regulación Leucémica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , Animales , Antígenos Ly/genética , Antígenos Ly/inmunología , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Quimiocina CXCL9/genética , Quimiocina CXCL9/inmunología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/patología , Modelos Animales de Enfermedad , Humanos , Inmunofenotipificación , Interleucina-10/genética , Interleucina-10/inmunología , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/patología , Macrófagos/inmunología , Macrófagos/patología , Ratones , Ratones Transgénicos , Monocitos/inmunología , Monocitos/patología , Cavidad Peritoneal/patología , Fenotipo , Receptores CCR2/genética , Receptores CCR2/inmunología , Transducción de Señal , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/patología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/patología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Chronic lymphocytic leukemia (CLL) remains incurable with chemoimmunotherapy, and allogeneic hematopoietic stem cell transplantation (HSCT) offers the potential for cure. We assessed the outcomes of 108 CLL patients undergoing first allogeneic HSCTs, 76 with reduced-intensity (RIC) and 32 with myeloablative conditioning (MAC) between 1998 and 2009 at Dana-Farber Cancer Institute. With median follow-up of 5.9 years in surviving patients, the 5-year overall survival (OS) for the entire cohort is 63% for RIC regimens and 49% for MAC regimens (P=0.18). The risk of death declined significantly starting in 2004, and we found that 5-year OS for HSCT between 2004 and 2009 was 83% for RIC regimens compared with 47% for MAC regimens (P=0.003). For RIC transplantation, we developed a prognostic model based on predictors of progression-free survival (PFS), specifically remission status, lactate dehydrogenase, comorbidity score and lymphocyte count, and found 5-year PFS to be 83% for Score 0, 63% for Score 1, 24% for Score 2 and 6% for Score ≥3 (P<0.0001). We conclude that RIC HSCT for CLL in the current era is associated with excellent long-term PFS and OS, and, as potentially curative therapy, should be considered early in the disease course of relapsed high-risk CLL patients.
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Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas , Leucemia Linfocítica Crónica de Células B/terapia , Modelos Estadísticos , Recurrencia Local de Neoplasia/terapia , Adulto , Anciano , Femenino , Citometría de Flujo , Estudios de Seguimiento , Humanos , Cariotipificación , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia , Acondicionamiento Pretrasplante , Trasplante HomólogoAsunto(s)
Proteínas de Unión al ADN/genética , Linfoma Folicular/genética , Mutación/genética , Recurrencia Local de Neoplasia/genética , Factores de Transcripción/genética , Adulto , Anciano , Anciano de 80 o más Años , Western Blotting , Estudios de Cohortes , Metilación de ADN , Proteína Potenciadora del Homólogo Zeste 2 , Epigénesis Genética , Femenino , Histonas , Humanos , Técnicas para Inmunoenzimas , Linfoma Folicular/diagnóstico , Linfoma Folicular/metabolismo , Lisina , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/metabolismo , Complejo Represivo Polycomb 2 , Pronóstico , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Análisis de Matrices Tisulares , Adulto JovenRESUMEN
CLL is extremely heterogeneous in its clinical course, with some patients living decades with no need for treatment whilst others have a rapidly aggressive clinical course. A major focus of research has been to try to identify those biological factors that influence this heterogeneity. The goal of therapy has been to maintain the best quality of life and treat only when patients become symptomatic from their disease. For the majority of patients this means following a "watch and wait" approach to determine the rate of progression of the disease and assess for development of symptoms. Any alteration to this approach will require identification of criteria that define patients sufficiently "high-risk" that they gain benefit by introduction of early therapy. The use of molecular profiling to suggest particular therapies is currently appropriate only in defining the treatment of the minority of patients with 17p deletions or p53 mutations and in all other circumstances remains a clinical trial question.
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Leucemia Linfocítica Crónica de Células B , Eliminación de Secuencia , Proteína p53 Supresora de Tumor , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/terapia , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Quantitative methylation profiling was performed using the Illumina GoldenGate Assay in untreated follicular lymphoma (FL) (164), paired pre- and post-transformation FL (20), benign haematopoietic (24) samples and purified B and T cells from two FL cases. Methylation values allowed separation of untreated FL samples from controls with one exception, based primarily on tumour-specific gains of methylation typically occurring within CpG islands. Genes that are targets for epigenetic repression in stem cells by Polycomb Repressor Complex 2 were significantly over-represented among hypermethylated genes. Methylation profiles were conserved in sequential FL and t-FL biopsies, suggesting that widespread methylation represents an early event in lymphomagenesis and may not contribute substantially to transformation. A significant (P<0.05) correlation between FL methylation values and reduced gene expression was shown for up to 28% of loci. Methylation changes occurred predominantly in B cells with variability in the amount of non-malignant tissue between samples preventing conclusive correlation with survival. This represents an important caveat in attributing prognostic relevance to methylation and future studies in cancer will optimally require purified tumour populations to address the impact of methylation on clinical outcome.
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Metilación de ADN , Perfilación de la Expresión Génica , Ganglios Linfáticos/patología , Linfoma Folicular/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Islas de CpG , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Adulto JovenRESUMEN
New insights into prognostic markers and the pathophysiology of chronic lymphocytic leukemia (CLL) are beginning to change the concept of CLL treatment. Alemtuzumab has evolved as a potent and effective therapeutic option for patients with CLL. Specifically, alemtuzumab has demonstrated substantial efficacy in fludarabine-refractory patients and has shown impressive responses when administered subcutaneously in first-line therapy. A group of experts gathered to discuss new data related to the use of alemtuzumab in CLL and to assess its place in the rapidly changing approach to treating patients with this disease. The main goals of this program were to update the management guidelines that were previously developed for alemtuzumab-treated patients and to provide community oncologists with guidance on the most effective way to integrate alemtuzumab into a CLL treatment plan.
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Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Alemtuzumab , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos/administración & dosificación , Manejo de la Enfermedad , Humanos , Leucemia Linfocítica Crónica de Células B/complicaciones , Leucemia Linfocítica Crónica de Células B/mortalidad , Guías de Práctica Clínica como Asunto , Resultado del TratamientoRESUMEN
Despite encouraging scientific and therapeutic advances, chronic lymphocytic leukemia (CLL) principally remains an incurable disease. Allogeneic transplantation represents the only curative approach, but is marked by high mortality. Novel and less toxic treatment modalities are needed. Immunotherapeutic approaches have clearly demonstrated potential effectiveness in CLL and other B-cell malignancies. To successfully direct immunity against CLL, highly immunogenic tumor cells or tumor-antigen-loaded antigen-presenting cells are necessary. The CD40-CD40L interaction has been shown to significantly increase antigen presentation in normal and malignant B-cells. Here we discuss biology and potential therapeutic applications of the CD40-system in CLL.
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Linfocitos B/inmunología , Antígenos CD40/inmunología , Leucemia Linfocítica Crónica de Células B/inmunología , Vacunación/métodos , Presentación de Antígeno/inmunología , Ligando de CD40/inmunología , Humanos , Leucemia Linfocítica Crónica de Células B/terapia , Activación de Linfocitos/inmunología , Transducción de Señal/inmunologíaRESUMEN
Nodal mantle cell lymphoma (MCL) is a well-defined entity, but non-nodal leukemic cyclin D1 positive lymphoproliferative disorders have been reported and their relationship with MCL remains controversial and their prognosis heterogeneous. We prospectively studied the expression of cyclin D1 in CD5 positive leukemic B lymphoproliferative disorders at diagnosis and identified 65 cases overexpressing cyclin D1. We did not distinguish any clinical or biological criteria allowing one to identify a non-MCL group. Multivariate analysis identified age, anemia and p27kip1 expression as independent prognostic factors of survival. By univariate analysis, p27kip1 high expression proved to be the strongest predictor of prolonged survival. The median survival of p27 low expressors was 30 months, while it was not reached for p27 high expressors. A high level of p27 expression was often found associated with the absence of nodal involvement and the presence of somatic mutations, but neither of them was restricted to the p27 high expression group. In conclusion, we hypothesize that MCL and these cyclin D1 positive leukemic lymphoproliferative disorders represent a continuous spectrum of diseases. Determination of p27 expression level appears as a routine applicable test allowing identification of a subset of patients who could be considered for different therapeutic approaches.
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Proteínas de Ciclo Celular/análisis , Ciclina D1/análisis , Trastornos Linfoproliferativos/metabolismo , Proteínas Supresoras de Tumor/análisis , Adulto , Anciano , Aberraciones Cromosómicas , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Femenino , Genes de Inmunoglobulinas , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Inmunofenotipificación , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/inmunología , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
One limitation of ASCT is the potential reinfusion of tumor cells contaminating PBSC. The Eligix B cell SC system consists of high-density microparticles coated with anti-B cell antibodies. To determine if this system eliminates B cells and lymphoma cells from PBSC, immunocytochemistry and PCR of the bcl-2/IgH rearrangement were performed, and correlated with patient outcome after ASCT. Eligible patients (n=29) had relapsed or transformed follicular NHL with bone marrow involvement <20%, and all lymph nodes <5 cm. PBSCs were mobilized with cyclophosphamide/G-CSF (n=21), and patients were conditioned with cyclophosphamide, carmustine and etoposide. Using immunocytochemistry on PBSC, the median number of CD20+ cells pre-purge was 310/10(6) (range 0-16692) and post-purge was 0.75/10(6); the median log B cell depletion was 2.7 (range 1.4-3.9). B cell depletion correlated with PFS after ASCT (P=0.06). Of 17 available samples for PCR, only four had a detectable t(14;18) breakpoint. After purging, all four remained PCR+; two had a 1-3 log depletion of lymphoma cells. At median follow-up of 18 months, 10 patients, including five infused with PCR-negative PBSC, have had disease progression. The paucity of PCR-informative patients, possibly related to in vivo rituximab therapy, limited the utility of minimal residual disease as a surrogate marker of clinical outcome.
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Linfocitos B , Depleción Linfocítica/métodos , Linfoma Folicular/patología , Linfoma Folicular/terapia , Trasplante de Células Madre de Sangre Periférica/métodos , Adulto , Anciano , Antígenos CD20/análisis , Eliminación de Componentes Sanguíneos/normas , Separación Celular/métodos , Progresión de la Enfermedad , Femenino , Supervivencia de Injerto , Humanos , Masculino , Persona de Mediana Edad , Células Neoplásicas Circulantes/patología , Análisis de Supervivencia , Trasplante Autólogo , Resultado del TratamientoRESUMEN
BACKGROUND: Autologous stem cell transplantation (SCT) has become the treatment of choice for patients with relapsed chemo-sensitive intermediate grade lymphoma, but its role in the treatment of low-grade lymphomas and in selected patients in first remission remains controversial. METHODS: A large number of clinical trials have evaluated the role autologous SCT in both low grade and intermediate grade non-Hodgkin's lymphomas (NHL). These studies have attempted to evaluate the role of high dose therapy with stem cell support in comparison to more conventional chemotherapy approaches. Studies have also focused on methods to assess whether contaminating tumor cells are contained with the stem cell collection and whether this has impact on outcome. With an increased number of patients now long term survivors, additional studies are focusing on long term complications and in particular the emergence of secondary malignancies. RESULTS: Virtually all patients now receive peripheral blood stem cells rather than bone marrow as a source of stem cells. The role of purging of residual tumor cells remains controversial and no randomized trial has been published to date that could evaluate the clinical utility of cell manipulation to attempt to remove contaminating lymphoma cells. Secondary leukemia is emerging as a major source of long-term morbidity and mortality after autologous stem cell transplantation. CONCLUSION: Autologous SCT is associated with improved outcome in patients with relapsed intermediate grade lymphoma and most likely prolongs disease free survival in patients with low grade NHL. Morbidity and mortality of the procedure is low and major efforts are being made to attempt to decrease the major causes of failure, which remain disease relapse and occurrence of secondary malignancies.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Linfoma/terapia , Acondicionamiento Pretrasplante , Trasplante de Médula Ósea , Ensayos Clínicos como Asunto , Genes de Inmunoglobulinas , Humanos , Linfoma/genética , Linfoma/patología , Linfoma/prevención & control , Neoplasia Residual , Receptores de Antígenos/genética , Recurrencia , Factores de Riesgo , Translocación Genética , Trasplante Autólogo , Trasplante HomólogoRESUMEN
Cytotoxic T-lymphocyte (CTL) responses can be generated against peptides derived from the immunoglobulin (Ig) V region in some but not all patients. The main reason for this appears to be the low peptide-binding affinity of Ig-derived peptides to major histocompatibility complex (MHC) class I molecules and their resulting low immunogenicity. This might be improved by conservative amino acid modifications at the MHC-binding residues of the peptides (heteroclitic peptides). In this study, it was found that in 18 Ig-derived peptides, that heteroclitic peptides from the Ig gene with improved binding to human leukocyte antigen (HLA)-A*0201 can be used to improve CTL responses. Amino acid substitution substantially increased predicted binding affinity, and there was a strong correlation between predicted and actual binding to HLA-A*0201. CTLs generated against the heteroclitic peptide had not only enhanced cytotoxicity against the heteroclitic peptide but also increased killing of antigen-presenting cells pulsed with the native peptide. Surprisingly, no difference was observed in the frequency of T cells detected by MHC class I peptide tetramers after stimulation with the heteroclitic peptide compared with the native peptide. CTLs generated against heteroclitic peptides could kill patients' tumor cells, showing that Ig-derived peptides can be presented by the tumor cell and that the failure to mount an immune response (among other reasons) likely results from the low immunogenicity of the native Ig-derived peptide. These results suggest that heteroclitic Ig-derived peptides can enhance immunogenicity, thereby eliciting immune responses, and that they might be useful tools for enhancing immunotherapy approaches to treating B-cell malignant diseases.
Asunto(s)
Antígeno HLA-A2/metabolismo , Idiotipos de Inmunoglobulinas/inmunología , Región Variable de Inmunoglobulina/inmunología , Leucemia de Células B/inmunología , Linfoma de Células B/inmunología , Proteínas de Neoplasias/inmunología , Fragmentos de Péptidos/inmunología , Linfocitos T Citotóxicos/inmunología , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Presentación de Antígeno , Sitios de Unión , Citotoxicidad Inmunológica , Antígeno HLA-A2/inmunología , Humanos , Idiotipos de Inmunoglobulinas/química , Región Variable de Inmunoglobulina/química , Región Variable de Inmunoglobulina/metabolismo , Proteínas de Neoplasias/química , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismoRESUMEN
A major obstacle for the development of cancer immunotherapy is the poor capacity of most tumor cells to present antigen. It has previously been shown that ligation of CD40 on the surface of malignant B cells results in the induction of efficient antigen presentation primarily because of upregulated expression of MHC, costimulatory, and adhesion molecules. Ongoing clinical trials are testing the impact of CD40 ligation as immunotherapy for B cell malignancies. Because CD40 is also widely expressed in carcinomas, we studied whether CD40 activation of these cells using soluble recombinant trimeric human CD40 ligand (srhCD40L) can also induce T cell responses. Here, we show that carcinoma cells upregulate expression of CD54 and MHC molecules following in vitro exposure to srhCD40L but do not upregulate CD80 or CD86. CD40-activated carcinoma cells failed to trigger mixed lymphocyte reactions, in sharp contrast to CD40-activated lymphoma cells for which CD40 activation, as expected, resulted in increased expression of MHC, adhesion, and costimulatory molecules, and generated brisk allogeneic lymphocyte reactions. Retroviral-mediated expression of CD80 in carcinoma cells, with or without CD40 activation, triggered mixed lymphocyte reactions, provided cells were treated with IFN-gamma. Thus, the cell surface phenotype induced on carcinoma cells following CD40 activation is not fully capable of inducing T cell proliferation; however, these results support ongoing efforts to exploit costimulation in clinical efforts aimed at increasing carcinoma immunogenicity.