T CELL THERAPY TARGETING MULTIPLE TUMOR ANTIGENS IN HODGKIN LYMPHOMA

针对霍奇金淋巴瘤多种肿瘤抗原的 T 细胞疗法

• 批准号: 8724175
• 负责人: Ann M. Leen
• 金额: $ 23.35万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8724175
• 关键词: Address; Adoptive Immunotherapy; Antigen Targeting; Antigen-Presenting Cells; Antigens; Azacitidine; Binding; Blood; CD8B1 gene; CTAG1 gene; Cancer Center; Cell physiology; Cells; Clinical; Clinical Research; Clinical Trials; Collaborations; Combined Modality Therapy; Complex; Cytokine Receptor Binding; Cytokine Receptors; Cytotoxic T-Lymphocytes; DNA; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; Development; Doctor of Medicine; Down-Regulation; EBV-Specific Cytotoxic T-Lymphocyte; Engineering; Environment; Epigenetic Process; Epitopes; Epstein-Barr Virus-Related Lymphoma; Frequencies; Funding; Future; Histone Deacetylase Inhibitor; Hodgkin Disease; Human Herpesvirus 4; IL4 gene; IL7 gene; Immune; Immunoassay; Immunocompetent; Immunosuppressive Agents; Immunotherapy; In Vitro; Individual; Interleukin 4 Receptor; Interleukin 7 Receptor; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Measures; Mediating; Medicine; Modeling; Mus; Outcome; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase I Clinical Trials; Pre-Clinical Model; Predisposition; Production; Reed-Sternberg Cells; Refractory; Relapse; Reproduction spores; Safety; Signal Transduction; Site; Specificity; Stimulus; T cell therapy; T-Lymphocyte; Testing; Training; Transgenic Organisms; Tumor Antigens; Tumor Escape; Viral; Viral Antigens; Virus; cancer cell; cell killing; cytokine; cytotoxic; immunogenic; immunogenicity; improved; in vitro activity; in vivo; killings; novel; novel strategies; peripheral blood; pressure; response; safety testing; survivin; tumor; tumor growth; tumor microenvironment

Tumor immunotherapy using EBV-specific cytotoxic T lymphocytes (CTLs) has been successful for the treatment of EBV-associated lymphomas arising in the immunocompetent host. However, the majority of referred patients have EBV-negative lymphomas, precluding the use of virus-targeted T cells; also, CTLs do not eliminate tumors in all patients, likely because potentially immunogenic tumors arising in immunocompetent persons develop immune evasion strategies that subvert the effector function of the infused CTLs. These include downregulation of viral antigens, and the production of soluble immunomodulatory cytokines, such as 1L4, from malignant and infiltrating inhibitory cells, which limit the in vivo activity of adoptively transferred T cells. To extend T cell therapy to all patients with Hodgkin lymphoma (HL), regardless of tumor EBV status, we used the previous SPORE funding cycle to develop a strategy to reactivate and expand CTLs with specificity for the nonviral tumor-associated antigens (TAAs) Survivin SSX2, MAGE-A4, NY-ESO-1 and FRAME expressed by malignant cells. We reasoned that targeting multiple TAAs simultaneously would minimize tumor immune escape and therefore are assessing the safety and efficacy of these multiTAA-CTLs in vivo. We now propose, in Project 1, to address two remaining barriers to successful T cell therapy, namely (a) low target antigen expression, and (b) the immunosuppressive tumor microenvironment. Thus, our central hypotheses are that the efficacy ot immunotherapy for HL can be enhanced by combination with epigenetic drugs and by modifying infused T cells to retain Thi function in the Th2 cytokine milieu of the tumor. Hence, in Aim 1 of our renewal application, in a phase I clinical trial, we will generate and infuse multiTAA-targeted CTLs in combination with a hypomethylating agent known to upregulate T cell target antigen expression on malignant cells and sensitize them to immune-mediated destruction. The impact of this combination therapy on tumor immunogenicity, T cell antitumor activity and epitope spreading will be assessed in Aim 2. Finally, Aim 3 seeks to protect adoptively transferred multiTAA-targeted CTLs from the tumor microenvironment by engineering the T cells to express a chimeric cytokine receptor that can bind the Th2 cytokine 1L4 and convert its inhibitory signal to one that is activating. Although restricted to preclinical models initially. Aim 3 will be clinically developed in the future. In summary, this approach combining drug therapy with tumorspecific CTLs may enable T cell immunotherapy to become more broadly applied to all patients with cancer.

使用EBV特异性细胞毒性T淋巴细胞（CTL）的肿瘤免疫疗法已经成功 免疫能力宿主中引起的EBV相关淋巴瘤的治疗。但是，大多数 推荐患者的EBV阴性淋巴瘤排除了靶向病毒的T细胞的使用；另外，CTL会这样做 并非所有患者中都消除肿瘤，这可能是因为潜在的免疫原性肿瘤 免疫能力的人会制定免疫逃避策略，以颠覆 注入CTL。这些包括病毒抗原的下调和可溶性的产生 来自恶性和浸润性细胞的免疫调节细胞因子，例如1L4，这限制了IN 经过转移的T细胞的体内活性。向所有霍奇金淋巴瘤患者扩展T细胞疗法 （HL），无论肿瘤EBV状态如何，我们都使用先前的孢子资金周期来制定策略 对非病毒肿瘤相关抗原（TAAS）Survivin的重新激活和扩展具有特异性的CTL SSX2，MAGE-A4，NY-ESO-1和由恶性细胞表达的框架。我们认为目标 多个TAA同时可以最大程度地减少肿瘤免疫逃生，因此正在评估安全性 这些多核CTL在体内的功效。现在，我们在项目1中建议解决剩下的两个 成功T细胞疗法的障碍，即（a）低靶抗原表达，（b） 免疫抑制肿瘤微环境。因此，我们的核心假设是IT的功效 HL免疫疗法可以通过与表观遗传药物结合并修饰来增强 注入的T细胞在肿瘤的Th2细胞因子环境中保留THI功能。因此，在我们的目标1中 续订应用，在I期临床试验中，我们将在中生成并注入靶向多靶标CTL 与已知上调T细胞靶抗原表达恶性肿瘤的降压剂的结合 细胞并将其敏感到免疫介导的破坏。这种组合疗法对肿瘤的影响 免疫原性，T细胞抗肿瘤活性和表位扩散将在AIM 2中评估。最后，AIM 3 旨在保护采用的多层靶向CTL免受肿瘤微环境的保护 工程T细胞表达可以结合Th2细胞因子1L4和的嵌合细胞因子受体 将其抑制信号转换为正在激活的信号。尽管最初仅限于临床前模型。目标3 将来会在临床上发展。总而言之，这种方法将药物治疗与特异性 CTL可以使T细胞免疫疗法更广泛地应用于所有癌症患者。