T cell therapy targeting multiple tumor antigens in lymphoma

针对淋巴瘤中多种肿瘤抗原的 T 细胞疗法

• 批准号: 10000865
• 负责人: Ann M. Leen
• 金额: $ 27.3万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000865
• 关键词: Address; Antigen Targeting; Antigenic Specificity; Antigens; Azacitidine; Biological; CTAG1 gene; Cell Line; Cell Therapy; Cell physiology; Cells; Clinical; Clinical Research; Combined Modality Therapy; Custom; Cytokine Receptors; Cytokine Signaling; DNA; Detection; Disease; Disease remission; Drug Sensitization; Engineering; Ensure; Environment; Epigenetic Process; Epitope spreading; Frequencies; Funding; Goals; HDAC4 gene; Histone Deacetylase Inhibitor; Hodgkin Disease; Human; IL4 gene; IL7 gene; Immune; Immune Targeting; Immune response; Immune system; Immunologics; Immunosuppression; Immunotherapy; Infusion procedures; Lead; Ligands; Link; Lymphoma; Malignant Neoplasms; Measurement; Measures; Mediating; Modeling; Modification; Mus; Non-Hodgkin' s Lymphoma; Outcome; Patients; Peer Review; Phase I Clinical Trials; Predisposition; Recurrent disease; Refractory; Refractory Disease; Regulatory T-Lymphocyte; Relapse; Reproducibility; Resistance; Signal Transduction; T cell therapy; T-Cell Proliferation; T-Lymphocyte; Technology; Testing; Therapeutic; Transgenic Organisms; Tumor Antigens; Tumor-Derived; antitumor effect; cancer cell; cancer immunotherapy; cancer type; cell killing; cytokine; design; engineered T cells; epigenetic therapy; flexibility; high risk; improved; improved outcome; in vitro testing; in vivo; liquid biopsy; neoplastic cell; novel strategies; peripheral blood; personalized medicine; phase I trial; preconditioning; recruit; response; safety and feasibility; serial imaging; success; survivin; targeted treatment; treatment effect; tumor; tumor DNA; tumor growth; tumor microenvironment; tumor specificity

Project Summary/Abstract Project 1 proceeds from its demonstration during the last funding cycle that T cells targeting 5 tumor-expressed antigens (PRAME, SSX2, MAGEA4, NY-ESO-1, and Survivin - multiTAA T cells) can be used to effectively treat relapsed/refractory Hodgkin and non-Hodgkin lymphoma. Indeed, 5 of 9 patients with active disease achieved durable compete remissions when infused with multiTAA T cells, an outcome that correlated with the detection of tumor-reactive T cells in peripheral blood. This renewal proposal is designed to improve on these results by addressing two remaining barriers to successful cancer immunotherapy: (a) immune escape due to low target antigen expression and (b) the hostile tumor microenvironment, which can subvert the effector function and limit the persistence of infused T cells. To enhance target antigen expression on malignant cells, we will precondition patients with a DNA hypomethylating agent, 5-azacytidine, that upregulates tumor-associated antigens (TAAs) and then relate the biological effects of treatment to subsequent clinical responses (Aims 1 and 2). We predict that the increased target antigen expression on malignant cells will enhance their killing by the adoptively transferred T cells and lead to more effective recruitment and activation of endogenous cellular immune responses, resulting in epitope spreading that will potentiate the antitumor effects of the multiTAA T cells and thus the clinical benefit to patients. In addition, to convert the hostile tumor milieu into one that promotes rather than inhibits T-cell function, we will engineer our multiTAA T cells to express customized inverted cytokine receptors (ICRs) designed to interact with immunosuppressive tumor-derived molecules (TGFꞵ and IL4) but deliver costimulatory and cytokine signals (4-1BB and IL7) that promote rather than inhibit T cell proliferation, activation, persistence and cytolytic activity (Aim 3). We predict that further benefit will derive from the sequestration of these suppressive tumor molecules, which would otherwise support tumor growth and survival while also polarizing the local environment towards inhibitory and tolerizing (Th2, Treg). Overall, we believe that these modifications will enable the wide introduction of a genuinely transformative cellular therapy for the treatment of relapsed/refractory lymphoma. This gain would not necessarily be limited to lymphoma; rather, the flexibility of the therapeutic strategy should enable the antigenic specificity of the engineered T cells to be tailored to each type of cancer under study.

项目摘要/摘要 项目1在最后一个融资周期中从其示范中进行，靶向5个肿瘤表达的T细胞 抗原（Prame，SSX2，MageA4，NY-ESO-1和Survivin-Multitaa T细胞）可用于有效治疗 复发/难治性的霍奇金和非霍奇金淋巴瘤。确实，有9例活跃疾病患者中有5例 耐用的竞争竞争时，当被多核T细胞感染时，这种结果与检测有关 外周血反应性T细胞的反应性T细胞。该更新建议旨在通过 解决成功癌症免疫疗法的剩余两个障碍：（a）由于目标较低而引起的免疫逃逸 抗原表达和（b）敌对的肿瘤微环境，可以颠覆效应子功能并限制 注入T细胞的持久性。为了增强恶性细胞上的靶抗原表达，我们将前提 DNA低甲基化剂5-氮杂丁胺的患者上调肿瘤相关抗原（TAAS） 然后将治疗的生物学作用与随后的临床反应联系起来（目标1和2）。我们预测 恶性细胞上增加的靶抗原表达将通过适当地增强其杀戮 转移T细胞并导致内源性细胞免疫的更有效募集和激活 响应，导致发作扩散，将潜在多核T细胞的抗肿瘤作用和 因此，对患者的临床益处。此外，将敌对的肿瘤环境转化为促进的肿瘤环境 而不是抑制T细胞功能，我们将设计我们的Multitaa T细胞以表达自定义的倒细胞因子 旨在与免疫抑制性肿瘤衍生分子（TGFꞵ和IL4）相互作用的接收器（ICR），但 传递促进而不是抑制T细胞增殖的共同刺激和细胞因子信号（4-1BB和IL7）， 激活，持久性和细胞溶解活性（AIM 3）。我们预测，进一步的好处将从 这些抑制性的肿瘤分子的隔离，否则将支持肿瘤生长和存活 同时也将局部环境朝向抑制和耐受性（TH2，Treg）。总体而言，我们相信 这些修改将使能够广泛引入真正的转化性细胞疗法 接力/难治性淋巴瘤的治疗。这种增益不一定仅限于淋巴瘤。而是 治疗策略的灵活性应使工程T细胞的抗原特异性量身定制 研究的每种类型的癌症。