El linfoma de Hodgkin es una neoplasia de células B caracterizada por la escasa presencia de células tumorales, células de Hodgkin/Reed-Sternberg, localizadas en un microambiente no tumoral. El comportamiento del LH se determina por las características intrínsecas de las células HRS y por las características de las células inflamatorias no neoplásicas del microambiente. Por eso, el análisis del papel pronóstico que juegan los miRNAs en el ganglio completo y no únicamente en las células tumorales adquiere un gran significado. La vía JAK/STAT es una vía de señalización utilizada por muchas citoquinas. La activación constitutiva de esta vía resulta de gran importancia en la patogénesis del LH. Se han descrito mutaciones puntuales en el gen JAK2 en síndromes mieloproliferativos; sin embargo, estas mutaciones son escasas en el LH, donde el aumento de la proteína JAK2 se asocia a amplificaciones del gen JAK2, mutaciones en genes reguladores como SOCS-1 o a una activación constitutiva de las proteínas STAT. Otro posible mecanismo que podría intervenir en la sobreexpresión de las proteínas JAK2 es la desregulación de miRNAs cuya función sea controlar la traducción de JAK2. La terapia estándar en LH es a base de antraciclina, con doxorubicina, bleomicina, vinblastina y dacarbacina (ABVD). A pesar de que el LH está considerado uno de los cánceres humanos más curable, con tasas de curación del 80-90%, el tratamiento de pacientes recaídos o con enfermedad refractaria, especialmente aquellos que recaen después de un autotrasplante de células madre, sigue siendo un reto. La FDA (US Food and Drug Administration) no ha aprobado nuevos tratamientos para el LH en los últimos 30 años. Por consiguiente, se necesitan nuevos fármacos, así como nuevas estrategias de tratamiento basadas en el conocimiento de la biología del LH y las vías de señalización implicadas, para mejorar el pronóstico de los pacientes. Lestaurtinib (CEP-701) es un inhibidor de tirosina quinasas con múltiples dianas. En estudios pre-clínicos, se ha demostrado que Lestaurtinib inhibe potentemente a FLT3 en concentraciones nanomolares. Por otra parte, estudios recientes han demostrado que la actividad inhibitoria de Lestaurtinib no se limita a FLT3 y puede suprimir la señalización de JAK2/STAT5 mediante la inhibición específica de JAK2 en SMP; sin embargo la eficiencia de Lestaurtinib en el LH permanece desconocida, aunque podría ser un fármaco de interés debido a las vías moleculares que inhibe, como la vía de JAK2/SAT5 que tan importante es en el LH. Basándonos en estas hipótesis, nos planteamos los siguientes objetivos: 1. Analizar si el patrón de expresión de microRNAs en ganglios linfáticos de pacientes afectos de LH tiene implicaciones pronósticas. 2. Determinar las vías a través de las cuales los miRNAs que actúan como marcadores pronósticos en LH están teniendo un papel clave. De forma específica: a. Determinar si JAK2 es un gen diana de miR-135a. b. Analizar si miR-135a está jugando un papel como gen supresor de tumor en el LH. 3. Analizar posibles acciones terapéuticas basadas en inhibidores de la vía de JAK2 en el LH. Específicamente: a. Evaluar la eficacia in vitro de Lestaurtinib (CEP701), un inhibidor de JAK2, en el LH. b. Evaluar la eficacia de Lestaurtinib en células primarias de ganglios de pacientes afectos de LH.

Diss. (sammanfattning) Göteborg : Univ., 2008. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Thesis (Ph. D.)--Cornell University, 1989. / Vita. Includes bibliographical references.

OBJECTIVE: The aim of this study was to investigate the safety and tolerability of a novel anti-folate drug, pemetrexed, in the setting of a phase I clinical trial in patients with non-HIV related central nervous system lymphoma (CNSL). METHODS: In this multicenter, open-label, phase I dose finding clinical trial, pemetrexed was investigated as a single agent treatment for primary or secondary CNSL. RESULTS: A total of 18 patients were enrolled between January 2009 and November 2014. The mean age was 64.6 years old (range: 47-79). The ratio of male to female was 1:1. One out of six patients experienced a dose limiting toxicity (DLT) at dose level 1 (600mg/m2). There were no DLTs among the four patients enrolled at dose level 2 (900m/m2). Two of six patients experienced a DLT at dose level 3 (1200mg/m2). The MTD was therefore determined to be 900mg/m2. Overall, pemetrexed was well tolerated but toxicities were seen and need to be monitored. All patients experienced at least one type of toxicity of any grade. Most patients (92.9%) experienced at least one type of neurological toxicity. Grade-3 toxicities included confusion, speech impairment, and psychosis. Twelve patients (85.7%) experienced at least one bone marrow type of toxicity of any grade. These toxicities included anemia (78.6%), thrombocytopenia (57.1%), neutropenia (50%), leukocytopenia (42.9%), and lymphopenia (42.9%). Four patients experienced either grade-3 (14.3%) or grade-4 (14.3%) neutropenia. Three patients experienced grade-3 leukopenia (21.4%). One patient experienced grade-3 lymphopenia (7.1%) and two patients experienced grade-4 lymphopenia (14.3%). Twelve patients (85.7%) experienced at least one metabolic type of toxicity of any grade. A majority of these were also grade-1 or 2, with the exception of hypophosphatemia (grade-4), hyperglycemia (grade-3) and increased ALT (grade-3), increased AST (grade-3) and increased creatinine phosphokinase (CPK) (grade-4). Constitutional and gastrointestinal symptoms were seen in >60% of patients. These consisted mainly of fatigue, constipation, nausea, and anorexia. Musculoskeletal symptoms were seen in greater than 60% of patients. Less common adverse events included pain (<60%), infection (<40%), dermatologic, ocular/visual, and pulmonary/upper respiratory (<30%). The average number of cycles on treatment for all patients was 5.5 cycles. 14 patients were evaluated for response to treatment by neuroimaging (MRI) while on treatment. Of these, four patients (28.6%) showed a complete response (CR). Of those patients, 2 patients achieved this response after only 2 doses, and 2 patients after a total of 8 doses. 5 patients (35.7%) showed a partial response (PR) and four patients (28.6%) achieved stable disease (SD). The overall response rate (ORR) was determined at 92.9% (SD, PR and CR combined). CONCLUSIONS: Given this data, pemetrexed is a powerful drug and feasible alternative to existing treatment options; however, certain toxicities need to be closely monitored. Further studies are needed to assess the efficacy of pemetrexed in a larger cohort of patients with CNSL.

Few cancers arising in fluid organ systems can be cured with localized therapeutic modalities, such as radiation or surgical organ removal. Chemotherapy and hematopoietic stem cell transplants have long been employed as the standard of care for patients diagnosed with leukemias and lymphomas. Though research continues to propose new, more potent chemotherapeutic agents, a new paradigm of treating cancerous malignancies with tumor-specific monoclonal antibodies, adoptively transferred tumor-fighting cells, and other exogenously administered immunomodulatory agents, has emerged over the past decade. These immunotherapies have dramatically improved the outcomes of patients diagnosed with cancers of B lymphocytes, referred to as B-cell malignancies. Though curative FDA-approved therapies for patients diagnosed with B-cell malignancies have yet to be established, recent research in the field of adoptive T-cell therapy has produced promising results. Tumor infiltrating lymphocyte therapy (TIL therapy), T-cell Receptor Therapy (TCR therapy) and Chimeric Antigen Receptor T-cell Therapy (CAR T-cell therapy) are the three most extensively studied adoptive T-cell immunotherapies in the context of B-cell malignancies. TIL and TCR therapies, in which patients are provided with either the patient’s own tumor-specific T-cells or T-cells expressing engineered, tumor-specific TCRs, respectively, enhance the patient’s immune system to mount a more potent, anti-tumor response. However, these adoptive T-cell therapies do not change the mechanisms of the immune response. Cancerous cells can evade immune attack and dampen immune responses to survive and thrive in the body. By down-regulating their expression of human major histocompatibility complex I (MHC I), for example, cancer cells escape T-cell recognition, which is dependent on MHC expression. A chimeric antigen receptor (CAR), is composed of an antibody-derived (B-cell derived) extracellular, antigen-recognition domain, and T-cell derived intracellular domains. CAR T-cells, therefore, exploit the cytotoxic nature of CD8+ T-cells, and the MHC independent recognition of B-cell receptors, to identify and destroy all cells expressing a specific target. Consequently, many of the cancer cell’s mechanisms of immune evasion are less effective in the presence of CAR T-cells. Progressive generations of CAR T-cell designs couple these receptors with costimulatory molecules to amplify the activation, efficacy, and potency of these cells in-vivo. Over the past five years, phase I and IIa clinical trials have produced remarkable results in the treatment of advanced stage, high-risk B-cell malignancies, namely Acute Lymphoblastic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), and Non-Hodgkin’s Lymphoma (NHL). However, the significant oncogenic risks and fatal adverse events associated with this therapy necessitate further research to improve safety and reliable clinical efficacy of CAR T-cell therapy. In spite of these risks, the adoptive transfer of CD19-targeting, CAR expressing, cytotoxic T-cells (anti-CD19 CAR-T-cells) has produced sustained, complete remissions in patients diagnosed with progressive, advanced-stage, B-cell malignancies, for whom alternative treatments were not available. The unprecedented results of early clinical trials, as well as ongoing preclinical studies aimed at improving the design and production of CAR T-cells suggest a promising future for CAR T-cell therapy as a cure for B-cell malignancies.

Orientador: Maura Moscardi Bacchi / Resumo: O linfoma de Hodgkin (LH) tem características clínicas e anátomo-patológicas distintas dos linfomas não-Hodgkin. Seu componente neoplásico, as células células de Hodgkin/Reed-Sternberg (H-RS), corresponde a cerca de 2% do tumor. As células H-RS apresentam imunofenótipo peculiar e sua origem ainda é objeto de estudo. O LH é classificado em LH clássico (que inclui os subtipos celularidade mista, esclerose nodular, depleção linfocítica e LH rico em linfócitos) e LH predominância linfocítica nodular. A associação do vírus de Epstein-Barr (EBV) com LH é conhecida e acredita-se que este vírus desempenha importante papel no desenvolvimento de parcela significativa dos casos de LH. No LH, o acúmulo de células reativas como linfócitos, plasmócitos, eosinófilos, histiócitos e fibroblastos ocorre em resposta a citocinas secretadas pelas células H-RS. A interleucina 10 (IL-10), importante citocina antiinflamatória da resposta imunitária, tem sido encontrada em grande quantidade em indivíduos com LH. É possível que essa elevada expressão de IL-10 esteja vinculada a determinados polimorfismos de nucleotídeos simples (SNP) na seqüência promotora do gene da IL-10, que podem se associar a características anátomoclínicas do LH. O presente trabalho avaliou a freqüência dos polimorfismos da IL-10 nas posições promotoras -1082, -819/-592 e estudou a correlação destes polimorfismos em LH com subtipos histológicos, infecção pelo EBV, faixa etária e, em alguns casos, estadiamento clínico da doença. Os resultados demonstram que os diferentes fenótipos para produção de IL-10, genótipos na posição -1082 e genótipos nas posições -592/-819 não têm relação com subtipos do LH e idade dos pacientes. Por outro lado, verificou-se que o genótipo GG na posição -1082 e a combinação de haplótipos GCC/GCC para alta... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Clinical and pathologic features of Hodgkin's lymphoma (HL) reflect an abnormal immune response, which is in part due to the elaboration of a variety of cytokines. It was reported that interleukin 10 (IL -10), which may be produced by the malignant Hodgkin/Reed-Sternberg (H-RS) cells, is an important prognostic factor in HL, and it could play a role in the pathogenesis of this neoplasm. It is well established that genetic factors affect protein expression and function. In this regard, polymorphisms in the promoter region of IL-10 gene may cause different phenotypes for IL- 10 synthesis and activity. Three dimorphic single nucleotide polymorphisms (SNPs) have been identified at positions -1082, -819 and -519 within the IL-10 promoter region (SNPs/IL-10). These polymorphisms are in close proximity to several transcription factors binding-sites, and may interfere with IL-10 gene transcription. The aim of this study was to evaluate whether is there a particular distribution of SNPs at positions -1082, -819 and -519 in the IL-10 gene promoter in patients with HL, as well as to access the differences in the SNPs/IL10 frequency regarding HL subtype, patient age, EBV infection status, and clinical staging of the disease. For these purposes, sixty-five cases of HL and fifty cases of reactive follicular lymphoid hyperplasia (RFLH) were evaluated for SNPs/IL-10 by polymerase chain reaction amplification plus restriction fragment length polymorphism analysis (PCR-RFLP). Compared to HL EBV-negative cases, in HL EBV-positive cases it was observed a significant increase in the frequency of GG genotype at position -1082 of IL-10 gene promoter region, which is associated to high level of IL -10 production. No differences were observed in the frequency of different SNPs/IL-10 concerning patient age, HL subtype, and clinical stage of the disease. These results... (Complete abstract, click electronic address below) / Mestre

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