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: 3194157
• 负责人: Martin Alexander Cheever
• 金额: $ 13.64万
• 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/3194157
• 关键词: CD3 molecule; CD4 molecule; T cell receptor; T lymphocyte; antiidiotype antibody; antitumor antibody; autologous transplantation; 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; CD3 molecule; CD4 molecule; T cell receptor; T lymphocyte; antiidiotype antibody; antitumor antibody; autologous transplantation; 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.

拟议项目的目的是开发刺激和 从具有恶性黑色素瘤和 识别和表征所识别的抗原。原则已经存在 在动物模型中开发，以消除通过 使用T细胞反应向肿瘤的产物传递。 中的一个 成功治疗的先决条件是大量的可用性 肿瘤反应性T细胞。 但是，有限的治疗功效 通过生长，可以大大增加少量肿瘤反应性T细胞 T细胞在体外并与T细胞数量增加一起处理。 许多研究小组表明，少数黑色素瘤 - 特异性T细胞存在于黑色素瘤患者中。 而且，尝试 用旨在通过增加的机制来治疗黑色素瘤 黑色素瘤反应性T细胞的数量是通过主动免疫的 黑色素瘤相关的抗原，或者通过黑色素瘤的过继转移 在体外产生的特定T细胞在A中取得了巨大成功 经过治疗的患者很小但确定的比例。 推断 动物模型，两个主要的问题抑制了更成功的应用 对人黑色素瘤的特定收养免疫疗法已足够 用于生成大量T细胞的培养系统，并保留 响应肿瘤而增殖和不足的能力 鉴定由自节体黑色素瘤识别的抗原 - 特定的T细胞。 这两个问题都可以通过关注 与CD8+ T细胞相反，CD4+ T细胞。 由于CD4+ T细胞是II类 MHC受限的CDR+ T细胞可以刺激以在体外增殖 对肿瘤或对可溶性肿瘤抗原的反应。 相比之下 CD8+ T细胞是I类MHC限制的，因此仅响应 由完整的肿瘤细胞提出的抗原合成。 因此，CD4+ 通过保留特异性，T细胞更容易长期生长， 特异性更容易验证，并且认识到的抗原是 非常容易识别和表征当前可用的 技术。 此外，肿瘤特异性CD4+ T细胞已被证明是 在某些特定肿瘤疗法中单独使用时极有效 动物模型，并且有可能能够介导消除肿瘤 通过直接溶解肿瘤和分泌多种淋巴细胞的分泌 可以直接和/或间接破坏肿瘤细胞。