HUMAN STUDIES

人类研究

• 批准号: 6300282
• 负责人: JEFFREY Y WONG
• 金额: $ 15.65万
• 依托单位: CITY OF HOPE NATIONAL MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6300282
• 关键词: antibody formation; antitumor antibody; bioimaging /biomedical imaging; carcinoembryonal antigen; chelating agents; clinical research; clinical trials; colon neoplasms; diethylenetriaminepentaacetate; gene expression; human subject; human therapy evaluation; hybrid antibody; immunocytochemistry; indium; interferon gamma; metastasis; neoplasm /cancer immunotherapy; neoplasm /cancer radionuclide therapy; neoplasm /cancer relapse /recurrence; pharmacokinetics; radiation therapy dosage; radiobiology; radionuclide imaging /scanning; radiopharmacology; yttrium

Radioimmunotherapy (RIT) demonstrates promise in laboratory models. This promise has been realized in the clinic for hematologic malignancies. For the more radioresistant solid tumors, results have been less successful, but remain encouraging. Dosimetry estimates and anti-tumor effects observed on current trials with the first generation of engineered agents indicate that clinically meaningfully results are close to being realized for solid tumors. To build on this promising base will require application of strategies that have proven successful in optimizing other systemic therapies; namely dose-intensification, to increase tumor dose, and multi-modality approaches, to increase the biologic effect of that targeted dose. The proposed therapy trials will evaluate these strategies in patients with CEA-producing malignancies. Upon completion of Phase I and Phase II studies evaluating 90Y-DOTA-anti-CEA chimeric T84.66, subsequent trials will evaluate 90Y anti-CEA RIT combined with 5- fluorouracil (5-FU) in colorectal cancer, combined with 5- FU/leucovorin/cis-platinum and stem cell support in chemo-responsive metastatic breast cancer, and combined with IP iododeoxyuridine in patients with peritoneal carcinomatosis. Combined modality trials will evolve towards therapy in patients which have been less heavily pre- treated, are chemo-responsive, and have lower tumor burden. These trials will provide an opportunity to further increase tumor responses by taking advantage of the radiation enhancing properties of these chemotherapy agents in a more favorable group of patients. Further improvements in radioimmunotherapy and radioimmunodetection will also require refinements of the antibody. Three intermediate molecular weight engineered constructs derived from T84.66 (F(ab')2 (110 kD), minibody (80 kD), and diabody, (55 kD)) will be evaluated in imaging and biodistribution trials radiolabeled with I-123. Due to faster clearance, their tumor/blood rations are superior to that of the intact, making them promising for further evaluation as imaging agents. The minibody, which demonstrates the highest tumor uptake and tumor/marrow dose rations, and a humanized version of T84.66 will also be evaluated as potential therapy agents initially in biodistribution trials labeled with In-111. These trials will provide the necessary foundation for future evaluation of improved constructs and chelates for therapy and imaging developed in project 2 (Bioengineered Antibodies) and Project B (Antibody Chelates and Conjugates).

放射免疫疗法（RIT）在实验室模型中表现出了希望。 这 在血液系统恶性肿瘤的诊所中已经实现了诺言。 为了 辐射耐药性实体瘤越少，结果就较不成功， 但是要保持鼓励。 剂量估计和抗肿瘤作用 在与第一代工程代理的当前试验中观察到 表明临床上有意义的结果接近实现 用于实体瘤。 以这个有希望的基础为基础 已证明成功地优化其他策略的应用 全身疗法；即剂量强化，以增加肿瘤剂量， 和多模式的方法，以增加生物学效应 目标剂量。 拟议的治疗试验将评估这些策略 在产生CEA的恶性肿瘤患者中。 第一阶段完成后 和II期研究评估90y-Dota-anti-Cea嵌合T84.66， 随后的试验将评估90y抗CEA RIT与5- 结直肠癌的氟尿嘧啶（5-FU）与5-结合 Fu/leucovorin/cis--铂和干细胞支持化学反应性。 转移性乳腺癌，并与IP碘脱氧尿苷合并 腹膜癌症患者。 联合模态试验将 进化为治疗的患者，而预先预先预先不那么严重 经过治疗，具有化学反应性，并且肿瘤负担较低。 这些试验 将提供机会通过服用进一步增加肿瘤反应 这些化学疗法的辐射增强特性的优势 一组更有利的患者中的代理商。 进一步改进 放射免疫疗法和放射免疫探测也将需要改进 抗体。 三个中间分子量工程 源自T84.66（F（AB'）2（110 KD），Minibody（80 KD）和的结构 Diabody（55 kd））将在成像和生物分布试验中评估 用I-123进行放射标记。 由于清除速度更快，它们的肿瘤/血液 口粮优于完整的口粮，使它们有望 作为成像剂的进一步评估。 小型近来证明 最高的肿瘤吸收和肿瘤/骨髓剂量口粮和人源化 T84.66的版本也将被评估为潜在的治疗剂 最初在标记为IN-111的生物分布试验中。 这些试验 将为将来评估改进提供必要的基础 项目2中开发的治疗和成像的结构和螯合物 （生物工程抗体）和项目B（抗体螯合物和 结合）。