SPECIFIC T CELL IMMUNITY TO AUTOLOGOUS MELANOMA

对自体黑色素瘤的特异性 T 细胞免疫

• 批准号: 3194158
• 负责人: Martin Alexander Cheever
• 金额: $ 14.27万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-12-01 至 1992-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3194158
• 关键词: CD3 molecule; CD4 molecule; T cell receptor; T lymphocyte; antiidiotype antibody; antitumor antibody; autologous transplantation; cellular immunity; disease /disorder model; immunogenetics; interleukin 2; killer cells; leukocyte activation /transformation; melanoma; model design /development; neoplasm /cancer immunodiagnosis; neoplasm /cancer immunotherapy; passive immunization; tissue /cell culture; tumor antigens

The goal of the proposed project is to develop methods to stimulate and grow melanoma-reactive T cells from individuals with malignant melanoma and to identify and characterize the antigens recognized. Principles have been developed in animal models for the eradication of established malignancy by use of the adoptive transfer of T cells reactive to the tumor. One of the prerequisites for successful therapy is the availability of large numbers of tumor-reactive T cells. However, the limited therapeutic efficacy of small numbers of tumor-reactive T cells can be greatly augmented by growing the T cells in vitro and treating with the increased number of T cells. Numerous research groups have demonstrated that small numbers of melanoma- specific T cells exists in patients with melanoma. Moreover, attempts to treat melanoma with regiments designed to function, in part, by increasing the number of melanoma-reactive T cells--either by active immunization with melanoma-associated antigens, or by the adoptive transfer of melanoma- specific T cells generated in vitro--have met with substantial success in a small but definite proportion of the patients treated. Extrapolating from animal models, two major problems inhibiting a more successful application of specific adoptive immunotherapy to human melanoma are in adequate culture systems for generating large number of T cells with retention of the ability to proliferate in response to tumor, and inadequate identification of the antigens recognized by autochthonous melanoma- specific T cells. Both problems are potentially solvable by focusing on CD4+ T cells, as opposed to CD8+ T cells. Since CD4+ T cells are class II MHC-restricted, CDR+ T cells can be stimulated to proliferate in vitro in response to tumor or in response to soluble tumor antigen. By contrast, CD8+ T cells are class I MHC-restricted and therefore only respond to antigen synthesized within the presented by intact tumor cells. Thus, CD4+ T cells are easier to grow long-term with retention of specificity, specificity is easier to validate, and the antigens recognized are exceedingly easier to identify and characterize by currently available technology. In addition, tumor-specific CD4+ T cells have been shown to be extremely effective when utilized alone in specific tumor therapy in some animal models, and are potentially capable of mediating tumor eradication by direct lysis of tumor and by secretion of a variety of lymphokines that can directly and/or indirectly destroy tumor cells.

拟议项目的目标是开发刺激和 从恶性黑色素瘤个体中培养黑色素瘤反应性 T 细胞， 识别和表征所识别的抗原。原则已 在动物模型中开发用于根除已确定的恶性肿瘤 利用对肿瘤有反应的 T 细胞的过继转移。 中的一个 成功治疗的先决条件是拥有大量的药物 肿瘤反应性 T 细胞。 但治疗效果有限 少量的肿瘤反应性 T 细胞可以通过生长而大大增加 体外 T 细胞并用增加数量的 T 细胞进行治疗。 许多研究小组已经证明，少数黑色素瘤 黑色素瘤患者体内存在特异性 T 细胞。 此外，还尝试 治疗黑色素瘤的治疗方案旨在部分通过增加 黑色素瘤反应性 T 细胞的数量——通过主动免疫 黑色素瘤相关抗原，或通过黑色素瘤的过继转移 体外产生的特异性 T 细胞在 接受治疗的患者比例虽小，但比例确定。 推断自 动物模型，两大问题阻碍更成功的应用 对人类黑色素瘤的特异性过继免疫疗法的研究处于充分状态 用于产生大量 T 细胞并保留 对肿瘤作出反应的增殖能力，以及不足 鉴定本地黑色素瘤识别的抗原 特异性T细胞。 这两个问题都可以通过关注来解决 CD4+ T 细胞，与 CD8+ T 细胞相反。 由于 CD4+ T 细胞属于 II 类 MHC 限制性 CDR+ T 细胞可在体外被刺激增殖 对肿瘤的反应或对可溶性肿瘤抗原的反应。 相比之下， CD8+ T 细胞是 I 类 MHC 限制性细胞，因此仅对 完整肿瘤细胞内合成的抗原。 因此，CD4+ T 细胞更容易长期生长并保留特异性， 特异性更容易验证，识别的抗原是 目前可用的非常容易识别和表征 技术。 此外，肿瘤特异性 CD4+ T 细胞已被证明 单独用于某些特定肿瘤治疗时非常有效 动物模型，并有可能介导肿瘤根除 通过直接裂解肿瘤和分泌多种淋巴因子 可以直接和/或间接破坏肿瘤细胞。