Lymphoma Studies

淋巴瘤是美国发病率和死亡率的一个重要原因，1994年有4万多例新病例，发病率约为每10万人中有16人。在20世纪40年代至80年代期间，淋巴瘤发病率的年增长率为4%，总体增长率为150%，这些统计数据进一步复杂化。此外，在大多数淋巴瘤细胞类型中，死亡率基本保持不变，每年约有19 000人死亡。我的研究兴趣是淋巴瘤和慢性白血病（CLL）的新治疗策略的临床发展。这些研究在几个方面补充了实验移植和免疫学（DETI）部门的总体使命。该部门的一个重点是开发血液疾病的新治疗方法，重点是通过免疫消融异体移植和疫苗驱动的自体细胞介导的抗肿瘤反应性的免疫方法。我的研究主要集中在新型药物，细胞因子和基于抗体的淋巴瘤治疗的发展，包括独特型疫苗的免疫治疗和同种异体移植期间t细胞免疫消融药物的评估。我临床工作的一个主要重点是开发新的治疗平台，治疗侵袭性淋巴瘤，这是该疾病类别中最常见的一个亚组。它们具有重要的临床意义，因为它们有可能治愈，但现有治疗方法的治愈率很低，并且对公共卫生构成重大风险。事实上，在过去的25年里，治愈率是否有了显著的提高是值得商榷的。我从耐药性的角度来研究这些疾病，并基于克服耐药性的策略开发了基于epoch的平台。然而，对已有可治愈办法的疾病的新治疗方法的发展存在必要的限制；就其本质而言，它们需要对经过验证的方案进行渐进式更改并逐步发展。我在EPOCH平台的开发中采用了这样的方法，首先是围绕体外研究和验证的临床概念构建方案，其次是通过从复发/难治性患者开始进行顺序临床试验。我最初的研究显示EPOCH在复发/难治性患者中具有高活性和良好的耐受性，并导致其在先前未治疗的侵袭性淋巴瘤中进一步改进和测试。后一项试验的结果显示，剂量调整EPOCH非常有效，可能优于CHOP，并导致CALGB研究在合作组环境中验证结果。这些研究还导致EPOCH平台与单克隆抗体和激酶抑制剂（LOI）联合的进一步发展，作为耐药性调节剂，并作为在独特型疫苗试验中实现细胞减少的平台，并在我们的免疫消融移植试验中消耗t细胞同时控制疾病。最近的研究结果表明，加入利妥昔单抗可能逆转bcl-2相关的耐药，并可能为利妥昔单抗与大b细胞淋巴瘤化疗的推定益处提供机制解释。我还将EPOCH平台的开发扩展到我们拥有长期成功合作关系的疾病实体，包括与艾滋病毒和艾滋病恶性肿瘤科（HAMB）合作治疗艾滋病毒相关淋巴瘤，与病理实验室合作治疗淋巴瘤样肉芽肿病（LYG）；这两项研究都产生了令人鼓舞的结果。值得注意的是，这些后一种疾病发生在免疫功能低下的患者身上，为免疫功能低下的疾病治疗提供了模型。与临床终点相一致的是多个实验终点，以帮助阐明耐药和药物作用机制，药代动力学和药效学，以及通过cDNA微阵列分析，癌基因表达，最小残留病（MRD）测量和免疫功能和反应进一步了解所研究疾病的病理生物学。我的第二个临床研究重点是淋巴瘤，慢性白血病和t细胞免疫消融术的新药物的开发。总的来说，这些是具有新作用机制的药物的I期和II期研究，对复发或难治性淋巴瘤患者开放。目前，我的兴趣是通过调节细胞凋亡作为化学增敏剂的药物，如单克隆抗体和蛋白激酶抑制剂。此外，我对鉴定和测试具有抗t细胞活性的药物感兴趣，努力开发用于免疫消融移植的t细胞耗竭的新方法。这些努力的重要组成部分包括药物药理和作用的研究，对t细胞功能和活力的影响，淋巴瘤和白血病的生物学，以及cDNA微阵列分析等高科技仪器的使用。我们最近提交了一份LOI，对蛋白酶体抑制剂PS-341在复发和难治性大b细胞淋巴瘤中的应用进行研究。Staudt博士实验室的研究表明，NF-Kappa-B在大b细胞淋巴瘤的活化b细胞样亚型中过度表达，预示着预后较差。因此，PS-341抑制这一途径可能会增加化疗的疗效。本研究的终点将是评估PS-341作为单一药物，评估其与化疗的毒性，并执行评估患者样本中NF-Kappa-B通路的分子终点，并将其与反应相关联。完成复发性淋巴瘤EPOCH化疗方案的开发和评估；显示淋巴瘤中p53突变、肿瘤增殖率和bcl-2表达与耐药的关系；完成未经治疗的大B细胞淋巴瘤剂量调整EPOCH的评估，中位随访40个月无进展生存率为74%。在未治疗的hiv相关淋巴瘤中完成剂量调整EPOCH的评估，在中位随访33个月时显示81%的无进展生存率和100%的无病生存率。显示化疗对hiv相关淋巴瘤CD4动态和病毒载量的影响，并评估hiv相关淋巴瘤化疗期间不接受抗逆转录病毒治疗的安全性。证实淋巴瘤样肉芽肿病（LYG）的病因是EBV-B细胞淋巴增生性疾病。评估与LYG相关的免疫缺陷并显示干扰素的有效性。评估升级9-氨基茶碱治疗复发性淋巴瘤的活性和毒性。获得CLL的cDNA微阵列分析和氟达拉滨作用的初步数据；提供了利妥昔单抗逆转大b细胞淋巴瘤bcl-2相关耐药的初步数据。参与了通过dna微阵列分析显示大b细胞淋巴瘤新分子亚型的研究。开始EPOCH联合利妥昔单抗治疗大b细胞淋巴瘤的试验&lt；BR&gt；显示动态给药对大b细胞淋巴瘤化疗药代动力学的影响。目前，我们正在开展在患者中使用硼替佐米的研究[摘要截短于7800个字符]

Lymphomas represent a significant cause of morbidity and mortality in the United States with over 40,000 new cases in 1994 and an incidence of approximately 16/100,000 population. These statistics are further compounded by the 4% annualized rise in the incidence of lymphomas with an overall 150% increase between the 1940s and 1980s. Furthermore, among most lymphoma cell types, mortality has remained largely unchanged at approximately 19,000 deaths per year. <BR>My research interest is in the clinical development of novel therapeutic strategies for lymphomas and chronic leukemias (CLL). These studies complement the overall mission of the Department of Experimental Transplantation and Immunology (DETI) in several ways. A focus of the Department is the development of novel treatments for hematologic diseases with one emphasis on immunological approaches through immunoablative allogeneic transplantation and vaccine driven autologous cell mediated anti-tumor reactivity. My research has focused on the development of novel drug, cytokine and antibody-based treatment of lymphomas and includes immune-based treatments with idiotype vaccines and evaluation of agents for T-cell immunoablation during allogeneic transplantation. <BR>A major focus of my clinical efforts is the development of novel treatment platforms for aggressive lymphomas, the single most common subgroup within this disease category. They are of major clinical interest because they are potentially curable, but at a low rate with available treatments, and represent a significant public health risk. Indeed, it is debatable if the incidence of cure has significantly improved over the past 25 years. I have approached these diseases from the perspective of drug resistance and developed the EPOCH-based platform based on strategies to overcome resistance. However, there are necessary constraints placed upon the development of new treatments for diseases in which there exists curable options; by their very nature, they require incremental changes to validated regimens and stepwise development. I have taken such an approach in the development of the EPOCH platform, first by constructing the regimen around in vitro studies as well as validated clinical concepts, and second through the conduct of sequential clinical trials beginning with relapsed/refractory patients. My initial study showed EPOCH to be highly active and well tolerated in relapsed/refractory patients, and led to its further modification and testing in previously untreated aggressive lymphomas. Results from this latter trial showed dose-adjusted EPOCH to be highly effective, and potentially superior to CHOP, and has led to a CALGB study to validate the results in a cooperative group setting. These studies have also led to the further development of the EPOCH platform in combination with monoclonal antibodies and kinase inhibitors (LOI), as resistance modulators, and as a platform to achieve cytoreduction in an idiotype vaccine trial, and to deplete T-cells while controlling disease in our immunoablative transplant trials. Recent results suggest that addition of rituximab may reverse bcl-2 associated drug resistance and may provide a mechanistic explanation for the putative benefit of rituximab with chemotherapy in large B-cell lymphomas. <BR>I have also extended the development of the EPOCH platform into disease entities in which we have longstanding and successful collaborative relationships, and include the treatment of HIV-associated lymphomas with the HIV and AIDS Malignancy Branch (HAMB) and the treatment of lymphomatoid granulomatosis (LYG) with the Laboratory of Pathology; both studies have produced encouraging results. Of note, these latter diseases occur in immunocompromised patients and provide models for the treatment of disease in immune depleted states. In concert with clinical endpoints are multiple experimental endpoints to help elucidate mechanisms of resistance and drug action, pharmacokinetics and pharmacodynamics, as well as to further understand the pathobiology of the diseases under study through cDNA microarray profiling, oncogene expression, measures of minimal residual disease (MRD), and immune function and response. <BR>My second clinical research focus is in the development of novel agents for lymphomas, chronic leukemias and T-cell immunoablation. In general, these are phase I and II studies of agents with novel mechanisms of action, which are open to patients with relapsed or refractory lymphomas. Presently, my interest is in agents which may act as chemo-sensitizers by modulating apoptosis, such as monoclonal antibodies and protein kinase inhibitors. Furthermore, I am interested in identifying and testing agents with activity against T-cells, in an effort to develop new approaches to T-cell depletion for immunoablative transplants. Important components of these efforts include the study of drug pharmacology and action, effects on T-cell function and viability, the biology of lymphomas and leukemias, and the use of high technology instruments such as cDNA microarray profiling. We have recently submitted a LOI to perform a study of the proteosome inhibitor, PS-341 in relapsed and refractory large B-cell lymphomas. Work from Dr. Staudt's laboratory shows overexpression of NF-Kappa-B in the activated B-cell like subtype of large B-cell lymphomas which portends are worse prognosis. Hence, inhibition of this pathway by PS-341 may increase the efficacy of chemotherapy. The endpoints of this study will be to assess PS-341 as a single agent, to assess its toxicity with chemotherapy and to perform molecular endpoints of evaluation of NF-Kappa-B pathways in patient samples and to correlate this with response. <BR><BR><BR>Accomplishments:<BR><BR> Completed development and evaluation of EPOCH chemotherapy in relapsed lymphoma<BR> Showed relationship between p53 mutation, tumor proliferation rate and bcl-2 expression, and drug resistance in lymphoma<BR> Completed evaluation of dose-adjusted EPOCH in untreated large B cell lymphomas and showed 74% progression-free survival at a median follow-up of 40 months. <BR> Completed evaluation of dose-adjusted EPOCH in untreated HIV-associated lymphomas and showed 81% progression-free survival and 100% disease-free survival at a median follow-up of 33 months. <BR> Showed effect of chemotherapy on CD4 dynamics and viral load in HIV-associated lymphomas, and assessed the safety of withholding antiretroviral treatment during chemotherapy for HIV-associated lymphomas<BR> Demonstrated the etiology of lymphomatoid granulomatosis (LYG) to be an EBV-B cell lymphoproliferative disorder. <BR> Assessed immunodeficiency associated with LYG and showed efficacy of interferon. <BR> Assessed activity and toxicity of escalated 9-aminocamptothecin in relapsed lymphomas. <BR> Obtained preliminary data on cDNA microarray profiling of CLL and effects of fludarabine.<BR> Provided preliminary data showing reversal of bcl-2 associated resistance by rituximab in large B-cell lymphomas. <BR> Participated in study showing new molecular subtypes of large B-cell lymphomas by cDNA-microarray profiling. <BR> Began a trial of EPOCH and rituximab in large B-cell lymphomas <BR> Showed effect of dynamic dosing on pharmacokinetics of chemotherapy for large-B cell lymphomas. Currently, we are opening studies employing bortezomib in mant [summary truncated at 7800 characters]