RADIOIMMUNOTHERAPY: CLINICAL STUDIES

项目1项目负责人：Wong，Jeffrey首席研究员：RaubltSChek，Andrew 产品说明： 使用γ-嵌合T84.66抗CEA的临床试验证明了联合免疫治疗的可行性和前景。 放射免疫治疗（RIT）与放射增强化疗。结果表明，临床意义 成果是可以实现的，当RIT被整合到其他既定的 小体积和亚临床疾病的治疗。结果还表明， 90 Y-cT 84.66是其免疫原性，这限制了治疗周期数。抗体的进一步改进 以及如何将RIT与其他已建立的疗法相结合。更有效地整合 将RIT纳入已建立的化疗和放疗方案，Aim的下一代I期和II期试验 将重点放在最有希望的领域，并评估以下策略：a）降低免疫原性， B）将RIT整合到已建立的、有活性的T84. 化疗和放疗/化疗方案，因此优化了额外化疗的临床影响。 关于Hdro\os es> for\f mrardi\ia^tiro\n t/o\ +tui m\rro\rr\r aQc/h*hieiav\a/abHleI^ wlAiti+hH **Y^V-_T8~Q4^.6R6R;<$aonrtdH c/N）\ttreoaott nr*or\n-fc*lhne <$*mrYo\f\-re&frao/c^t+ortri'vw，somaolll v%o/rltuli mimea 疾病，其中放射性标记抗体的肿瘤摄取预计是最高的，并且临床影响 最棒的临床试验将评估1）RIT作为一线多药化疗的额外组成部分， 新诊断为转移性疾病的结直肠癌患者; 2）RIT作为肝转移的附加成分 动脉化疗在结直肠癌患者疾病切除后谁是亚临床， 隐匿性区域和远处转移;和3）RIT作为整合到既定放射治疗中的附加治疗 CEA+局部晚期、手术不可切除的非小细胞肺癌的化疗方案， 尽管有常规治疗，仍有局部和远处复发的高风险。这些试验还将提供 评价抗血管生成抗体贝伐单抗对90 Y-T84.66肿瘤的作用的独特机会 摄取，以评估iriln-贝伐单抗的肿瘤靶向和药代动力学，并最终评估其潜力 作为RIT的候选抗体。目标2中的试验将评估乳腺癌中针对HER 2的RIT。在这个 研究机构，曲妥珠单抗，放射性标记的111 ln，已证明肿瘤靶向和器官剂量测定 与cT84.66相当，证明了其在用90 Y标记的I期治疗试验中的评价。这将是一个 一项I期试验，将Y-曲妥珠单抗RIT整合到已确立的化疗方案中，治疗 转移性乳腺癌曲妥珠单抗由于其抗肿瘤作用而具有对RIT有吸引力的性质， 放射/化学疗法增强作用和最小免疫原性。

Project 1 Project Leader: Wong, Jeffrey Principal Investigator: RaubltSChek, Andrew DESCRIPTION: Clinical trials with ^Y-chimeric T84.66 anti-CEA demonstrate the feasibility and promise of combining radioimmunotherapy (RIT) with radiation-enhancing chemotherapy. Results indicate that clinically meaningful outcomes are achievable, with the greatest promise expected when RIT is integrated into other established therapies in the setting of small volume and subclinical disease. Results also show that the primary limitation of 90Y-cT84.66 is its immunogenicity, which limits the number of therapy cycles. Further refinements in the antibody and in how RIT is combined with other established therapies are therefore needed. To more effectively integrate RIT into established chemotherapy and radiotherapy regimens, the next generation of Phase I and II trials in Aim will focus on the most promising areas and evaluate strategies which: a) reduce the immunogenicity of the antibody, by utilizing a less immunogenic humanized version of T84.66; b) integrate RIT into established, active chemotherapy and radiation/chemotherapy regimens and therefore optimize the clinical impact of the additional pr^artial Hdro\os¿es> fo\f mrardi\ia^tiro\n t/o\ +tui m\rro\rr\r aQc/h*hieiav\a/abHleI^ wlAiti+hH **Y^V-_T8~Q4^.6R6R;¿aonrtdH c/N) \ttreoaott nr*or\n-fc*lhne¿*mrYo\f\-re&frao/c^t+ortri'vw, somaolll v%o/rltuli mimea disease, where the tumor uptake of radiolabeled antibody is expected to be the highest and the clinical impact the greatest. Clinical trials will evaluate 1) RIT as an additional component of front-line multi-agent chemotherapy in colorectal cancer patients with newly diagnosed metastatic disease; 2) RIT as an added component to hepatic arterial chemotherapy in colorectal cancer patients after disease resection who are at high risk of subclinical, occult regional and distant metastases; and 3) RIT as an additional therapy integrated into an established radiation and chemotherapy regimen for CEA+ locally advanced, surgically un-resectable non-small cell lung cancer, who are at high risk of local and distant recurrence despite conventional therapies. These trials will also provide the unique opportunity to evaluate the effects of the anti-angiogenesis antibody, bevacizumab, on 90Y-T84.66 tumor uptake, to assess tumor targeting and pharmacokinetics of iriln-bevacizumab and to ultimately assess its potential as a candidate antibody for RIT. Trials in Aim 2 will evaluate RIT directed against HER2 in breast cancer. At this institution, trastuzumab, radiolabeled with 111ln, has demonstrated tumor targeting and organ dosimetry comparable to cT84.66, justifying its evaluation in a phase I therapy trial labeled with 90Y. This will be followed by a phase I trial which integrates Y-trastuzumab RIT into an established chemotherapy regimen in patients with metastatic breast cancer. Trastuzumab has properties that make it attractive for RIT due to its anti-tumor effects, radiation/chemotherapy enhancing effects, and minimal immunogenicity.