RADIOIMMUNOTHERAPY: CLINICAL STUDIES

项目1项目负责人：黄健锋首席调查员：RaubltSChek，Andrew 说明： Y嵌合T84.66抗CEA的临床试验证明了联合应用的可行性和前景 放射免疫治疗(RIT)配合放射增强化疗。结果表明，在临床上有意义。 结果是可以实现的，当RIT整合到其他已建立的项目中时，预计会有最大的希望 小体积和亚临床疾病背景下的治疗。结果还表明，最主要的限制是 90Y-cT84.66是其免疫原性，限制了治疗周期。抗体的进一步改进 以及如何将RIT与其他已有的疗法相结合，因此是必要的。更有效地整合 RIT进入现有的化疗和放射治疗方案，在AIM进行下一代I期和II期试验 将重点放在最有希望的领域并评估以下战略：a)降低 抗体，通过利用免疫原性较低的人源化版本的T84.66；b)将RIT整合到已建立的、活跃的 化疗和放射/化疗方案，从而优化额外的临床影响 Pr^arartial Hdro-oséos；fo\f mrardi t/o tui m\rro\rr\r AQC/h*hieiav\a/abHleI^wlAiti+HH**Y^V-_T8~Q4^.6R6R；C/N)\ttreoaott nr*or\n-fc*lhne¿*mrYo\f\-re&frao/c^t+ortri‘vw，Somaolll v%o/rltuli Mimea 肿瘤对放射性标记抗体的摄取预计是最高的，其临床影响 太棒了。临床试验将评估1)RIT作为一线多药化疗的附加成分 新诊断为转移性疾病的结直肠癌患者；2)RIT作为肝脏的附加成分 动脉化疗在结直肠癌术后亚临床高危患者中的应用 隐匿性的区域和远处转移；以及3)RIT作为一种附加治疗整合到已建立的放射治疗中 CEA+局部晚期、不能手术切除的非小细胞肺癌的化疗方案，世卫组织 尽管采用传统的治疗方法，但局部和远处复发的风险很高。这些试验还将提供 评价抗血管生成抗体贝伐单抗对90Y-T84.66肿瘤作用的难得机会 摄取，以评估伊利兰-贝伐单抗的肿瘤靶向性和药代动力学，并最终评估其潜力 作为RIT的候选抗体。AIM 2的试验将评估针对乳腺癌HER2的RIT。对此 用111ln放射性标记的机构曲妥珠单抗已经证明了肿瘤靶向和器官剂量测定。 与cT84.66相当，在标记为90Y的I期治疗试验中证明其评估是合理的。这之后将是一个 将Y-曲妥珠单抗RIT整合到已建立的化疗方案中的I期试验 转移性乳腺癌。曲妥珠单抗具有抗肿瘤作用，因此对RIT具有吸引力， 放化疗增强效果，免疫原性最低。

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.