NEW TUMOR MODELS FOR THE DEVELOPMENT OF IMMUNOTHERAPY

全国抗癌模型合作发展小组(NCAMDG) 一项提案旨在开发一种新的人类自发转移模型 恶性黑色素瘤探索有效治疗癌症的策略 这使得我们能够深入调查日益增长的 转移性肿瘤和人类免疫系统。这款车型将是 建立在患有遗传免疫缺陷的小鼠身上，这是 注射人外周血白细胞(SCID-HU)。此外，这一点 一项提案寻求在《无性系》中利用同样的转移模型 (NU//NU)小鼠，在目前可操作的情况下，并比较 疗效，这两种抗癌模式开发了新的癌症治疗方法 医疗模式。具体地说，这两种抗癌模型将有助于 批判性评价人鼠嵌合细胞的抗增殖作用 抗表皮生长受体的单抗 因子(EGF-R)和黑素转铁蛋白(MTR)；新型嵌合 抗体-白介素2和肿瘤坏死因子融合蛋白， 识别EGF-R或MTR和T细胞标志物的双特异性抗体，如 CD3、CD2及嵌合单抗重组融合蛋白 以及假单胞菌外毒素的细胞毒域。这件事的参与者 合作协议包括麻省理工学院的科学家 斯克里普斯诊所，加利福尼亚州拉荷亚和达蒙生物技术公司，马萨诸塞州尼达姆高地。 这些科学家在研究中的密切合作卓有成效 抗神经节苷脂抗原的嵌合重组单抗已经导致 与临床中心合作进行的I期临床试验 生物反应调节剂计划。项目I提出了一个 概述和行政预算。项目II涉及 嵌合重组单抗和新型融合蛋白的研究进展 由嵌合的单抗和细胞因子或生长因子组成。在项目III中 建立SCID-HU自发性转移瘤模型 小鼠，并与已在无菌(nu/nu)中运行的相同模型进行比较 老鼠。项目3和项目4也涉及到这些鼠标的优化 系统作为转移性疾病的抗癌模型及其评价 不同杂合嵌合抗体融合抗肿瘤作用的研究 蛋白质。预计拟议的实验将导致 新的抗癌模式和可以 在未来的I期临床试验中对这些嵌合单抗和 他们的重组构建物在体内显示出抗肿瘤作用的前景 人恶性黑色素瘤自发转移的新动物模型。

This NATIONAL COOPERATIVE ANTI-CANCER MODEL DEVELOPMENT GROUP (NCAMDG) proposal seeks to develop a new, spontaneous metastasis model of human malignant melanoma to explore strategies for effective cancer treatment that allows an in-depth investigation of the interactions between a growing metastatic tumor and the human immune system. This model will be established in mice with genetically determined immunodeficiency, that are injected with human peripheral leukocytes (SCID-hu). In addition, this proposal seeks to make use of this same metastasis model in athymic (nu//nu) mice, where it is presently operative, and to compare the efficacy, of these two anti-cancer models to develop new cancer treatment modalities. Specifically, the two anti-cancer models will serve to critically evaluate the antiproliferative effects of chimeric mouse-human monoclonal antibodies (chMabs) against receptors for epidermal growth factor (EGF-R) and melanotransferrin (MTr); novel chimeric antibody-interleukin-2 and tumor necrosis factor fusion proteins, bispecific antibodies recognizing EGF-R or MTr and T cell markers such as CD3 and CD2, and recombinant fusion proteins consisting of chimeric Mabs and the cytotoxic domain of Pseudomonas exotoxin. The participants in this cooperative agreement include scientists from the Research Institute of Scripps Clinic, La Jolla, CA and Damon Biotech, Inc., Needham Heights, MA. Close productive collaborations between these scientists in studies with chimeric recombinant Mabs to ganglioside antigens have already led to clinical phase I trials in collaboration with clinical centers selected by the Biological Response Modifier Program, NCI. Project I presents an overview and an administrative budget. Project II deals with the development of chimeric recombinant Mabs and novel fusion proteins, consisting of chimeric Mab and cytokines or growth factors. In Projects III and IV, the spontaneous metastatic tumor model will be developed in SCID-hu mice and compared to the same model already operative in athymic (nu/nu) mice. Both, Projects 3 and 4 also deal with the optimization of these mouse systems as anti-cancer models of metastatic disease and with the evaluation of anti-tumor effects of the various hybrid chimeric antibody-fusion proteins. It is anticipated that the proposed experiments will lead to novel anti-cancer models and to new cancer treatment modalities that can be evaluated in future phase I clinical trials with those chimeric Mabs and their recombinant constructs that show promise of anti-tumor effects in novel animal models of spontaneous metastasis of human malignant melanoma.