TARGETING CHEMORESISTANT TUMOR-INITIATING CELLS IN CLL

靶向 CLL 中的化疗耐药肿瘤起始细胞

• 批准号: 8921122
• 负责人: Aaron E. Foster
• 金额: $ 22.09万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8921122
• 关键词: Adopted; Antigens; Autologous; Autologous Tumor Cell; B lymphoid malignancy; Blood Circulation; Cancer Vaccines; Cells; Chronic Lymphocytic Leukemia; Clinical Research; Clinical Trials; Clinical Trials Design; Complement; Cytotoxic T-Lymphocytes; Disease; Drug resistance; Funding; General Population; Goals; Hematopoietic stem cells; Human; Immunization; Immunotherapy; Injection of therapeutic agent; Interleukin-2; Lead; Lymphatic Diseases; Lymphoma; Marrow; Methods; Mus; Outcome; Pathogenesis; Patients; Peptides; Population; Process; Property; Regulatory T-Lymphocyte; Reporting; Reproduction spores; Resistance; Resolution; Role; Safety; Secondary Immunization; Side; Splenomegaly; T cell response; T-Lymphocyte; TNFSF5 gene; Testing; Time; Transgenic Organisms; Vaccination; Vaccines; base; cancer cell; cancer initiation; clinically relevant; cytokine; genetically modified cells; improved; in vivo; leukemia/lymphoma; leukemic stem cell; mouse model; neoplastic cell; overexpression; precursor cell; progenitor; targeted cancer therapy; therapeutic target; tumor; vaccine response

The long-term goal of Project 4 is to develop an effective, clinically feasible approach to targeting chemoresistant tumor-initiating cells in chronic lymphocytic leukemia (CLL). In the preceding SPORE funding period, we showed that a small subset of circulating or marrow-resident CLL cells within the side population (SP) of tumor cells are drug resistant and have properties associated with cancer initiation. After demonstrating that a tumor vaccine consisting of autologous tumor cells modified to express IL-2 and CD40L could generate a T cell response (vaccine-induced cytotoxic T cells, or VICTs), directed primarily against the SP subset of CLL cells, we now propose to use this information to prepare T cells directed against the SP-associated antigens we previously identified, using ex vivo peptide immunization (Peptide-induced Cytotxic T cells- PICTs). We will also test a strategy for enhancing these T cell responses against the drug resistant and putative tumor initiating SP cells, by genetically modifying the SP-directed T cells to express IL-21, thus rendering them resistant to Treg cell inhibition. We will also administer the modified T cells together with continued "booster" vaccination with peptides to increase T cell expansion and persistence in vivo. These new strategies will be tested in NSG mice engrafted with CLL cells (Alms 1 and 2). In Aim 3 we plan to conduct a clinical trial (Aim 3) that will evaluate the most successful approach emerging from the CLL mouse model. The outcome of this project should provide a new and effective means of targeting, chemoresistant CLL-initiating cells, hence complementing extant methods of eradicating bulk populations of non-SP tumor cells. More broadly, it will confimi the existence of clinically relevant subset of CLL progenitors and demonstrate the feasibility of using immunotherapy to target these cells.

项目4的长期目标是开发一种有效的、临床上可行的靶向方法。 慢性淋巴细胞性白血病（CLL）中的化疗耐药肿瘤起始细胞。前项 在SPORE资助期间，我们发现一小部分循环或骨髓中的CLL细胞 肿瘤细胞侧群（SP）内的肿瘤细胞具有耐药性，并具有与以下相关的特性 癌症起始。在证明了由自体肿瘤细胞组成的肿瘤疫苗 经修饰表达IL-2和CD 40 L可产生T细胞应答（疫苗诱导的细胞毒性T细胞 细胞，或VICTs），主要针对CLL细胞的SP子集，我们现在建议使用这种 制备针对我们先前鉴定的SP相关抗原的T细胞的信息， 使用离体肽免疫（肽诱导的细胞增殖T细胞- PICTs）。我们还将测试 增强这些T细胞对耐药和推定肿瘤的应答的策略 启动SP细胞，通过遗传修饰SP导向的T细胞以表达IL-21，从而使 它们对Treg细胞抑制有抗性。我们还将给予修饰的T细胞， 用肽继续“加强”接种以增加体内T细胞扩增和持久性。 这些新策略将在移植有CLL细胞的NSG小鼠中进行测试（Alms 1和2）。在目标3 我们计划进行一项临床试验（目标3），以评估出现的最成功的方法 来自CLL小鼠模型。该项目的成果应提供一种新的有效手段， 的靶向，化学抗性的CLL-起始细胞，因此补充了现有的方法， 根除非SP肿瘤细胞的大量群体。更广泛地说，它将证实 CLL祖细胞的临床相关子集，并证明使用免疫疗法的可行性 来瞄准这些细胞。