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：
8782611
负责人：
BRENDA MARIE SANDMAIER
金额：
$ 63.48万
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 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8782611
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 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

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 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

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项目摘要

DESCRIPTION (provided by applicant): Anti-CD20 monoclonal antibodies (MAb) radiolabeled with β-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 β-emitters in RIT due to the short path length and high cytotoxicity of α-emissions. The overall goal of this project is to overcome these limitations by delivering targeted anti-CD45 radiotherapy using an α-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（由适用提供）：用β-发射体标记的抗CD20单克隆抗体（MAB）可以在65-90％的非霍奇金淋巴瘤（NHL）患者的65-90％中恢复常规化疗。但是，大多数用这些mAB治疗的患者随后缓解。造血细胞移植（HCT）是转传NHL患者的一种选择，但是由于疾病复发，这种方法经常失败。由于大多数药物的非特异性性质，加强制备的方案减少救济的方法受到毒性的限制。我们已经表明，肿瘤的患者在放射免疫疗法（RIT）后接受较高的吸收剂量放射线的可能性较小。然而，尽管取得了成功，但毒性很重要，并非所有NHL患者都使用与HCT结合的靶向RIT策略来治愈。此外，CD20阴性NHL的患者（例如T细胞NHL）不会受益于针对CD20抗原的治疗的靶向增强。放射标记的抗CD45 mAb作为HCT的调节方案的一部分，用于中继的髓样疾病，但尚未在NHL方案中测试NHL，即使NHL> 95％表达了CD45抗原，也没有接受过测试。我们最近开始探索131I-ANTI-CD45 MAB，以改善HCT中接力NHL患者的预后，但是毒性仍然很高，治愈率是次优的。由于α-发射体的短路径长度和高细胞毒性，α发射器是RIT中β发射体的有吸引力替代品。该项目的总体目标是通过使用α-发射极（Astatine-211（211AT））提供靶向抗CD45放射疗法来克服这些局限性，并在具有赞助淋巴瘤的狗的疾病部位。我们预测，这种有效的治疗方案将放射性残留疾病（MRD），并降低HCT后毒性较小后的缓解风险。在AIM 1中，我们将定义最佳抗 CD45 mAb蛋白剂量用于靶向B-和T细胞NHL狗的CD45。我们预计，优化的抗CD45 mAb剂量将针对大多数靶向CD45表达细胞，同时放大正常组织。在AIM 2中，我们将使用AIM 1中确定的优化蛋白质剂量作为犬固结疗法在先前的抗NHL化学疗法后缓解中确定的优化蛋白质剂量来评估211AT标记的抗CD45-MAB的效率和毒性。尽管这种方法将有望消除MRD并改善狗的缓解中的生存率，但用于复发的NHL的抗CD45 RIT的理论剂量可能需要HCT，因为在大多数造血细胞上表达了CD45。因此，在AIM 3中，我们将研究以NHL的犬类中的自体HCT，然后在升级的剂量中进行可行性，安全性和效率F 211AT标记的抗CD45 MAB。最后，在AIM 4中，我们将通过211AT标记的抗CD45 mAb和同种异体HCT评估RIT的相对优点，以通过将这种方法进一步扩展到DLA-sedical-nedical和单倍体犬，以治愈NHL。我们预计，这些研究的信息将允许使用211AT-ANTI-CD45 MAB快速转换为NHL的临床RIT HCT计划。