Immunology of CLL I--Active immunotherapy & autologous stem cell transplantation

CLL I 的免疫学--主动免疫治疗

• 批准号: 6259046
• 负责人: Thomas J Kipps
• 金额: $ 4.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6259046
• 关键词: CD antigens; CD40 molecule; T lymphocyte; antigen presenting cell; autologous transplantation; cell line; cell transplantation; chronic lymphocytic leukemia; clinical research; cytotoxic T lymphocyte; genetic manipulation; human tissue; immunoglobulins; immunotherapy; molecular cloning; stem cells

The central hypothesis of this proposal is that there exist leukemia- associated antigens that can induce host anti-leukemia immunity resulting in leukemia-cell clearance. Furthermore, we hypothesize that because of the leukemia cell phenotype, such leukemia-specific T cells exist in a state o f anergy, thereby precluding effective immune-mediated clearance of the leukemic clone. Finally, we hypothesize that methods that alter this phenotype, or that induce immunity against leukemia-associated antigens, will provide novel and effective therapeutic strategies for patients with this disease. To examine this, we have the following specific aims: (1) Evaluate the potential for immunotherapy using autologous leukemia cells that have been: (A) genetically-modified to express recombinant CD40- ligand (CD154); or (B) induced to express immune co-stimulatory molecules through CD40-ligation ex vivo; (2) Determine the capacity of professional antigen presenting cells (APCs) to present B-CLL Ig specific antigens to induce anti-B-CLL specific immunity in vitro and in vivo by: (A) cloning and expressing the leukemia specific Ig; (B) identifying the putative peptide sequences from the B-CLL specific Ig rearrangements; (C) pulsing APCs with B-CLL specific Ig and Ig peptides; and (D) attempting to generate Ig specific cytotoxic T cells (CTL) using professional APCs pulsed with B-CLL specific Ig and Ig peptides; (3) examine the expressed T cell receptor V beta repertoires of blood T cells, T cell subsets, anti-leukemia CTL cell lines, and CD4+ T cells, or CD4+ T cell subsets expanded via CD3/CD28 ligation in vitro; (4) Undertake autologous stem cell transplantation (SCT) to address the impact on clinical outcome of : (A) purging; or (B) high dose myeloablative therapy; and (5) Determine the feasibility, safety, and efficacy of treating minimal residual disease following conventional therapy and autologous SCT using: (A) genetically modified CLL cells to express recombinant CD154; (B) CLL cells activated via CDE40 ex vivo; or (C) professional APC pulsed with B-CLL specific Ig and/or peptides. Through these studies we will test the hypothesis that patients with CLL can develop cellular immune recognition of their leukemia cells that potentially may be effective in the treatment of this disease.

该提议的中心假设是存在白血病相关抗原，可以诱导宿主抗白血病免疫，从而导致白血病细胞清除。 此外，我们假设由于白血病细胞表型，此类白血病特异性T细胞以无反应状态存在，从而阻碍了白血病克隆的有效免疫介导清除。 最后，我们假设改变这种表型或诱导针对白血病相关抗原的免疫力的方法将为患有这种疾病的患者提供新颖且有效的治疗策略。 为了研究这一点，我们有以下具体目标：（1）评估使用自体白血病细胞进行免疫治疗的潜力，这些细胞已经：（A）经过基因改造以表达重组CD40-配体（CD154）； (B)通过离体CD40连接诱导表达免疫共刺激分子； (2) 通过以下方法确定专职抗原呈递细胞 (APC) 呈递 B-CLL Ig 特异性抗原以在体外和体内诱导抗 B-CLL 特异性免疫的能力： (A) 克隆和表达白血病特异性 Ig； (B) 从 B-CLL 特异性 Ig 重排中鉴定推定的肽序列； (C) 用 B-CLL 特异性 Ig 和 Ig 肽脉冲 APC； (D) 尝试使用用 B-CLL 特异性 Ig 和 Ig 肽脉冲的专业 APC 生成 Ig 特异性细胞毒性 T 细胞 (CTL)； (3)检测血液T细胞、T细胞亚群、抗白血病CTL细胞系以及CD4+T细胞或体外通过CD3/CD28连接扩增的CD4+T细胞亚群表达的T细胞受体Vβ库； (4) 进行自体干细胞移植 (SCT)，以解决以下因素对临床结果的影响： (A) 清除； (B) 高剂量清髓治疗； (5) 确定常规治疗和自体 SCT 治疗微小残留病的可行性、安全性和有效性： (A) 表达重组 CD154 的转基因 CLL 细胞； (B) 通过 CDE40 离体激活的 CLL 细胞； (C) 用 B-CLL 特异性 Ig 和/或肽脉冲的专业 APC。 通过这些研究，我们将检验以下假设：CLL 患者可以对其白血病细胞产生细胞免疫识别，这可能有效治疗这种疾病。