Alpha Radioimmunotherapy for Lymphoma Treatment

淋巴瘤治疗的阿尔法放射免疫疗法

基本信息

批准号：
8420091
负责人：
JOHN M PAGEL
金额：
$ 67.94万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8420091
关键词：
Ablation Allogenic Astatine Autologous B-Lymphocytes Binding Sites Bone Marrow CD20 Antigens CD45 Antigens Canis familiaris Cardiotoxicity Cells Clinical Clinical Data Clinical Trials Combination Drug Therapy Consolidation Therapy Data Disease Disease remission Disease-Free Survival Disorder by Site Dose Dose-Limiting Drug Kinetics Engraftment Exposure to Goals Health Heart Hematologic Neoplasms Hematopoietic Hematopoietic Neoplasms High Dose Chemotherapy Immunosuppression Label Length Lung Lymphoma MS4A1 gene Malignant Neoplasms Marrow Modeling Monoclonal Antibodies Monoclonal Antibody CD20 Myeloproliferative disease Myelosuppression Nature Non-Hodgkin&apos s Lymphoma Normal tissue morphology Occupations Organ Outcome PTPRC gene Patients Proteins Radiation Radiation therapy Radioimmunoconjugate Radioimmunotherapy Radioisotopes Radiolabeled Recurrence Refractory Regimen Relapse Relative (related person)Research Residual Neoplasm Risk Safety Spleen Stem cell transplant Stem cells T-Cell Lymphoma Testing Therapeutic Tissues Toxic effect Translations Treatment Protocols Treatment outcome Whole-Body Irradiation chemotherapy conditioning cytotoxicity effective therapy hematopoietic cell transplantation improved lymph nodes novel novel strategies older patient pre-clinical programs radiation absorbed dose radiotracer rituximab success tumor

项目摘要

DESCRIPTION (provided by applicant): Anti-CD20 monoclonal antibodies (MAb) radiolabeled with b-emitters can achieve remissions in 65-90% of non-Hodgkin lymphoma (NHL) patients failing conventional chemotherapy. However, most patients treated with these MAbs subsequently relapse. Hematopoietic cell transplantation (HCT) is an option for relapsed NHL patients, but this approach frequently fails because of disease recurrence. Intensifying the preparative regimen to reduce relapse has been limited by toxicities due to the non-specific nature of most agents. We have shown that patients whose tumors receive higher absorbed doses of radiation are less likely to recur after radioimmunotherapy (RIT). Despite successes, however, the toxicities are significant and not all NHL patients are cured using targeted RIT strategies combined with HCT. In addition, patients with CD20 negative NHL, such as T-cell NHL, do not benefit from targeted intensification of therapy directed at the CD20 antigen. Radiolabeled anti-CD45 MAbs have been highly effective as part of a conditioning regimen for HCT for relapsed myeloid diseases, but have not been tested in regimens for NHL even though >95% of NHL express the CD45 antigen. We have recently begun exploring 131I-anti-CD45 MAb to improve outcomes for relapsed NHL patients in the setting of HCT, but toxicity remains high and cure rates are suboptimal. Alpha emitters are an attractive alternative to the ?-emitters in RIT due to the short path length and high cytotoxicity of a- emissions. The overall goal of this project is to overcome these limitations by delivering targeted anti-CD45 radiotherapy using an ?-emitter, astatine-211 (211At), to sites of disease in dogs with spontaneous lymphoma. We predict that this effective treatment regimen will eradicate minimal residual disease (MRD) and decrease the risk of relapse after HCT with less toxicity. In Aim 1 we will define the optimal anti CD45 MAb protein dose for targeting CD45 in dogs with B- and T-cell NHL. We anticipate that the optimized anti-CD45 MAb dose will target the majority of targeted CD45 expressing cells while sparing normal tissues. In Aim 2 we will assess the efficacy and toxicities of 211At-labeled anti-CD45-MAb using the optimized protein dose determined in Aim 1 as consolidation therapy for canines in remission after prior anti-NHL chemotherapy. Although this approach will be expected to eliminate MRD and improve survival for dogs in remission, therapeutic doses of anti-CD45 RIT for relapsed NHL will likely require HCT as CD45 is expressed on most hematopoietic cells. Therefore, in Aim 3 we will investigate the feasibility, safety, and efficacy f 211At-labeled anti-CD45 MAb in escalating doses followed by autologous HCT in canines with NHL. Finally, in Aim 4 we will assess the relative merits of RIT with 211At-labeled anti-CD45 MAb and allogeneic HCT to cure NHL by further extending this approach to both DLA- identical and haploidentical dogs. We anticipate that the information from these studies will allow rapid translation of the optimized promising RIT strategy using 211At-anti-CD45 MAb into our clinical RIT HCT program for NHL.

描述（由申请人提供）：用 b 发射体放射性标记的抗 CD20 单克隆抗体 (MAb) 可以使 65-90% 常规化疗失败的非霍奇金淋巴瘤 (NHL) 患者获得缓解。然而，大多数接受这些单克隆抗体治疗的患者随后都会复发。造血细胞移植（HCT）是复发性NHL患者的一种选择，但这种方法经常因疾病复发而失败。由于大多数药物的非特异性，加强准备方案以减少复发受到毒性的限制。我们已经证明，肿瘤接受较高辐射吸收剂量的患者在放射免疫治疗（RIT）后复发的可能性较小。然而，尽管取得了成功，但毒性仍然很大，并且使用靶向 RIT 策略结合 HCT 并非所有 NHL 患者都能治愈。此外，CD20 阴性 NHL（例如 T 细胞 NHL）患者无法从针对 CD20 抗原的靶向强化治疗中获益。放射性标记的抗 CD45 MAb 作为复发性骨髓疾病 HCT 预处理方案的一部分非常有效，但尚未在 NHL 方案中进行测试，尽管 > 95% 的 NHL 表达 CD45 抗原。我们最近开始探索 131I-抗 CD45 单克隆抗体，以改善 HCT 背景下复发 NHL 患者的预后，但毒性仍然很高，治愈率也不佳。由于α发射体的路径长度短且细胞毒性高，α发射体是RIT中α发射体的有吸引力的替代品。该项目的总体目标是通过使用β-发射体砹211 (211At) 对患有自发性淋巴瘤的狗的疾病部位进行靶向抗 CD45 放射治疗来克服这些限制。我们预测这种有效的治疗方案将根除微小残留病（MRD）并降低 HCT 后复发的风险，且毒性较小。在目标 1 中，我们将定义最佳反 CD45 MAb 蛋白剂量用于靶向患有 B 细胞和 T 细胞 NHL 的狗的 CD45。我们预计优化的抗 CD45 MAb 剂量将靶向大多数目标 CD45 表达细胞，同时不影响正常组织。在目标 2 中，我们将使用目标 1 中确定的优化蛋白质剂量来评估 211At 标记的抗 CD45-MAb 的功效和毒性，作为先前抗 NHL 化疗后缓解的犬的巩固治疗。尽管这种方法有望消除 MRD 并提高缓解期狗的生存率，但治疗复发 NHL 的抗 CD45 RIT 剂量可能需要 HCT，因为 CD45 在大多数造血细胞上表达。因此，在目标 3 中，我们将研究 211At 标记的抗 CD45 MAb 在 NHL 犬中递增剂量随后进行自体 HCT 的可行性、安全性和有效性。最后，在目标 4 中，我们将通过进一步将此方法扩展到 DLA 相同和单倍体相同的狗，评估 RIT 使用 211At 标记的抗 CD45 MAb 和同种异体 HCT 治疗 NHL 的相对优点。我们预计这些研究的信息将允许将使用 211At-抗 CD45 MAb 的优化的有前景的 RIT 策略快速转化为我们的 NHL 临床 RIT HCT 计划。