Alpha Radioimmunotherapy for Lymphoma Treatment

描述（由申请人提供）：用b-发射器放射标记的抗cd20单克隆抗体（MAb）可以在65-90%的常规化疗失败的非霍奇金淋巴瘤（NHL）患者中实现缓解。然而，大多数接受这些单克隆抗体治疗的患者随后复发。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。我们已经表明，患者的肿瘤接受较高的辐射吸收剂量后，不太可能复发放射免疫治疗（RIT）。然而，尽管取得了成功，但毒性是显著的，并不是所有的NHL患者都能通过靶向RIT策略联合HCT治愈。此外，CD20阴性NHL患者，如t细胞NHL，不能从针对CD20抗原的靶向强化治疗中获益。放射标记的抗CD45单克隆抗体作为复发性髓系疾病HCT治疗方案的一部分非常有效，但尚未在NHL治疗方案中进行测试，尽管约95%的NHL表达CD45抗原。我们最近开始研究131I-anti-CD45 MAb，以改善HCT背景下复发性NHL患者的预后，但毒性仍然很高，治愈率也不理想。α发射器是一种有吸引力的替代？在RIT中，由于a-排放物的短路径长度和高细胞毒性。这个项目的总体目标是克服这些限制，通过提供靶向抗cd45放射治疗使用？-发射器，砹-211 (2111at)，在自发性淋巴瘤犬的疾病部位。我们预测，这种有效的治疗方案将根除微小残留病（MRD），降低HCT后复发的风险，而且毒性更小。在目标1中，我们将定义最优反

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. PUBLIC HEALTH RELEVANCE: The high-dose chemotherapy or total body irradiation needed to prepare patients with lymphoma (or other cancers) for blood stem cell transplantation cannot be used in older patients or patients with additional health concerns. This application proposes to develop a preparative regimen that delivers radiation primarily to the cancer, thereby reducing whole body toxicity. These studies have the potential to provide a major advancement in the treatment outcome of many patients with relapsed lymphoma.