SPORE in Lymphoma

描述（由申请人提供）：贝勒医学院和卫理公会医院淋巴瘤孢子的总体目标是在实验室中设计，并在临床上验证干预策略，其广泛目标是改善霍奇金淋巴瘤和非霍奇金淋巴瘤以及慢性淋巴细胞白血病（CLL）的结局。我们计划的基本主题是，需要增加对淋巴瘤细胞基本生物学的理解，以推动这组恶性肿瘤的新疗法的开发。贝勒和卫理公会医院的实验室和临床研究人员组成的多学科团队将通过明智地整合他们目前的研究兴趣来实现这一目标。在项目1中，Rooney和Bollard博士将验证霍奇金淋巴瘤中的新靶抗原，特别是癌症睾丸抗原，然后在复发性疾病患者中测试对这些靶点特异性的细胞毒性T淋巴细胞（CTL）。项目2中的Dotti和Brenner博士计划在表达K阳性免疫球蛋白的滤泡性淋巴瘤患者中测试经工程改造以表达抗K轻链抗体（作为嵌合受体）的T细胞，目的是改善CTL对肿瘤细胞的识别。他们还提出将两种对相同CTL具有不同细胞毒性模式的B细胞靶向部分联合收割机以增强修饰的T细胞对肿瘤细胞的杀伤。由Gottschalk和Heslop博士领导的项目3的主要目的是通过扩大CTL的肿瘤特异性并通过疫苗接种提供额外的抗原来增加其在患者中的扩增来改善EBV阳性霍奇金淋巴瘤和非霍奇金淋巴瘤的结局。项目4将利用肿瘤免疫学中的一个新兴概念-肿瘤微环境中T调节（Treg）细胞的负面影响可以削弱CTL或其他免疫疗法的抗肿瘤活性。因此，Drs Wang和Mims将评估使用特异性配体激活Treg细胞上的Toll样受体是否可以减轻或逆转这些细胞的抑制功能，从而释放T细胞介导的抗肿瘤免疫的潜力。最后，在项目5中，Brenner和Goodell博士基于CLL疫苗研究中的观察结果，将测试CLL可能含有癌症干细胞的假设，这些癌症干细胞的定义分子可以被靶向用于更有效的治疗干预。这些项目中的每一个都是明确的翻译，解决了双向途径中出现的问题，最初来自临床观察（项目3和5）或实验室发现（项目1，2和4）。计划建立五个核心以满足该SPORE的专业要求：管理、临床研究、生物统计学和数据管理、细胞和载体生产以及组织库。淋巴瘤孢子还将支持发展研究计划和职业发展计划，以促进试点翻译项目和研究兴趣集中在淋巴瘤的年轻研究人员的进步。

DESCRIPTION (provided by applicant): The overall goal of the Lymphoma SPORE at Baylor College of Medicine and The Methodist Hospital is to devise in the laboratory, and validate in the clinic, interventional strategies, with the broad objective of improving outcome in Hodgkin's and non-Hodgkin's lymphomas and in chronic lymphocytic leukemia (CLL). The underlying theme of our program is that increased understanding of the fundamental biology of lymphoma cells is needed to drive the development of novel therapies for this group of malignancies. A multidisciplinary team of laboratory and clinical investigators at Baylor and The Methodist Hospital will pursue this goal through judicious integration of their current research interests. In Project 1, Drs. Rooney and Bollard will validate new target antigens in Hodgkin's lymphoma, particularly cancer testis antigens, before testing cytotoxic T lymphocytes (CTLs) specific for these targets in patients with relapsed disease. Drs. Dotti and Brenner in Project 2 plan to test T cells engineered to express anti-K-light-chain antibody, as a chimeric receptor, in patients with follicular lymphomas expressing K-positive immunoglobulins, with the aim of improving tumor cell recognition by the CTLs. They also propose to combine two B-cell-targeting moieties with distinct modes of cytotoxicity on the same CTL to enhance tumor cell killing by the modified T cells. The principal aim of Project 3, led by Drs. Gottschalk and Heslop, is to improve outcome in EBV-positive Hodgkin's and non-Hodgkin's lymphomas by broadening the tumor specificity of CTLs and increasing their expansion in patients by providing additional antigen by vaccination. Project 4 will exploit an emerging concept in tumor immunology - that the negative effects of T-regulatory (Treg) cells in the tumor microenvironment can blunt the antitumor activity of CTLs or other immunotherapies. Thus, Drs Wang and Mims will evaluate whether the activation of Toll-like receptors on Treg cells, using specific ligands, can lessen or reverse the suppressive function of these cells, thus releasing the potential of T-cell-mediated immunity against the tumor. Finally, in Project 5, Drs. Brenner and Goodell, building on observations in a CLL vaccine study, will test the hypothesis that CLL may harbor, cancer stem cells whose defining molecules could be targeted for more productive therapeutic interventions. Each of these projects is clearly translational, addressing issues that arose in a bidirectional pathway, initially either from observations in the clinic (Projects 3 and 5) or from laboratory findings (Projects 1, 2 and 4). Five cores are planned to meet the specialized requirements of this SPORE: Administration, Clinical Research, Biostatistics and Data Management, Cell and Vector Production, and Tissue Bank. The Lymphoma SPORE will also support a Developmental Research Program and a Career Development Program to foster the advancement of pilot translational projects and of young investigators whose research interests focus on lymphoma.