SPECIFIC IMMUNOTHERAPY OF MURINE TUMORS

小鼠肿瘤的特异性免疫治疗

• 批准号: 6172096
• 负责人: Martin Alexander Cheever
• 金额: $ 27.86万
• 依托单位: CORIXA CORPORATION
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6172096
• 关键词: B lymphocyte; CD antigens; CD22 molecule; T cell receptor; T lymphocyte; athymic mouse; cell differentiation; cellular immunity; colony stimulating factor; complementary DNA; cytotoxic T lymphocyte; genetic polymorphism; graft versus host disease; helper T lymphocyte; human genetic material tag; human tissue; leukemia; lymphoma; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; phenotype; tissue /cell culture; transfection /expression vector; vaccinia virus

DESCRIPTION: (Applicant's Abstract) Leukemia and lymphoma usually do not recur in patients who develop graft-vs.-host disease (GVHD) following allogeneic bone marrow transplantation (BMT). Donor T cell populations that mediate GVHD can also mediate a graft-vs.-leukemia (GVL) effect that is commonly curative. Unfortunately, GVHD is difficult to control and often fatal. This application proposes to determine whether polymorphic segments of abundant hematopoietic differentiation antigens can serve as GVL targets. Leukemia therapy with T cells specific for antigens expressed only by hematopoietic cells might be curative without GVHD toxicity. The applicant's preliminary data show that T cells specific for polymorphic segments of CD45, and abundant differentiation antigen on all hematopoietic cells, can be elicited by immunization to peptides derived from polymorphic segments and can mediate vigorous responses against host lymphocytes and leukemia cells. The proposed experiments will determine whether T cells specific for polymorphic segments of CD45 and other abundant polymorphic hematopoietic differentiation antigens can mediate T cell therapy of leukemia and lymphoma without GVHD. The focus will be on therapy of B cell malignancies. The Specific Aims are: 1) To target T cell therapy against polymorphic segments of CD45; 2) To target T cell therapy against polymorphic segments of CD22; 3) To target T cell therapy against polymorphic segments of CD72; 4) To determine whether CD45, CD22, and CD72 are polymorphic in humans; 5) To compare therapy directed against the B cell differentiation antigens expressed by all B cells (CD22 and CD72) to antigens expressed by only subsets of B cells (polymorphic segments of the constant region of Ig heavy chain) and 6) To treat B cell malignancy in autologous hosts using autologous T cells transfected with T cell receptor (TCR) alpha and beta chains specific for polymorphic hematopoietic differentiation antigens.

描述：（申请人摘要）白血病和淋巴瘤通常不会 发生移植物抗宿主病 (GVHD) 的患者在以下情况下会复发 同种异体骨髓移植（BMT）。 供体 T 细胞群 介导 GVHD 也可介导移植物抗白血病 (GVL) 效应 这通常是有疗效的。 不幸的是，GVHD 很难控制 并且常常是致命的。 本申请建议确定是否 丰富的造血分化抗原的多态性片段 可以作为GVL目标。 使用特异性 T 细胞进行白血病治疗 仅由造血细胞表达的抗原可能具有治愈性，无需 GVHD 毒性。 申请人的初步数据显示，T细胞 特异性针对 CD45 多态性片段，并且具有丰富的分化能力 所有造血细胞上的抗原，可以通过免疫接种来引发 衍生自多态性片段的肽，可以介导剧烈的 针对宿主淋巴细胞和白血病细胞的反应。 拟议的 实验将确定 T 细胞是否具有多态性特异性 CD45 片段和其他丰富的多态性造血片段 分化抗原可以介导白血病的T细胞治疗 无 GVHD 的淋巴瘤。 重点将放在 B 细胞治疗上 恶性肿瘤。 具体目标是： 1) 靶向 T 细胞治疗 对抗 CD45 的多态性片段； 2）靶向T细胞治疗 对抗 CD22 的多态性片段； 3）靶向T细胞治疗 对抗 CD72 的多态性片段； 4) 判断是否CD45, CD22 和 CD72 在人类中具有多态性； 5) 比较定向治疗 针对所有 B 细胞表达的 B 细胞分化抗原 （CD22 和 CD72）仅由 B 细胞亚群表达的抗原 (Ig重链恒定区的多态性片段)和6) 使用自体 T 细胞治疗自体宿主的 B 细胞恶性肿瘤 用 T 细胞受体 (TCR) α 和 β 链特异性转染 用于多态性造血分化抗原。