Alpha Radioimmunotherapy for Lymphoma Treatment

描述（由申请方提供）：用b-发射体放射性标记的抗CD 20单克隆抗体（MAb）可在65-90%常规化疗失败的非霍奇金淋巴瘤（NHL）患者中实现缓解。然而，用这些MAb治疗的大多数患者随后复发。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。我们已经证明，接受较高吸收剂量放射治疗的肿瘤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，但毒性是显著的，并且并非所有NHL患者都使用靶向RIT策略与HCT组合治愈。此外，患有CD 20阴性NHL（例如T细胞NHL）的患者不能从针对CD 20抗原的靶向强化治疗中获益。放射性标记的抗CD 45单克隆抗体作为用于复发性骨髓疾病的HCT的预处理方案的一部分是高度有效的，但尚未在用于NHL的方案中进行测试，即使>95%的NHL表达CD 45抗原。我们最近开始探索131 I-抗CD 45单克隆抗体，以改善在HCT设置复发NHL患者的结果，但毒性仍然很高，治愈率是次优的。阿尔法发射器是一个有吸引力的替代？-由于α-发射的短路径长度和高细胞毒性，该项目的总体目标是通过使用？-放射性核素211 At，对自发性淋巴瘤犬的病变部位。我们预测，这种有效的治疗方案将消除微小残留病（MRD），降低HCT后复发的风险，毒性较小。在目标1中，我们将定义最佳反 在患有B细胞和T细胞NHL的犬中靶向CD 45的CD 45 MA B b蛋白剂量。我们预计，优化的抗CD 45单抗剂量将靶向大多数靶向CD 45表达细胞，同时保留正常组织。在目标2中，我们将使用目标1中确定的优化蛋白剂量评估211 At标记的抗CD 45-MAb作为既往抗NHL化疗后缓解的犬的巩固治疗的疗效和毒性。尽管这种方法有望消除MRD并改善缓解期犬的生存率，但治疗剂量的抗CD 45 RIT治疗复发性NHL可能需要HCT，因为大多数造血细胞上表达CD 45。因此，在目标3中，我们将研究递增剂量的211 At标记的抗CD 45单克隆抗体随后在患有NHL的犬中进行自体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该方法扩展到DLA-相同和单倍体相同的狗来评估使用211 At-标记的抗-CD 45 MAb和同种异体HCT的RIT治疗NHL的相对优点。我们预计，这些研究的信息将允许使用211 At-抗CD 45单克隆抗体的优化的有前途的RIT策略快速翻译到我们的临床RIT HCT计划NHL。 公共卫生相关性：为淋巴瘤（或其他癌症）患者准备血液干细胞移植所需的高剂量化疗或全身照射不能用于老年患者或有其他健康问题的患者。本申请提出开发一种制备方案，其主要向癌症递送辐射，从而降低全身毒性。这些研究有可能为许多复发性淋巴瘤患者的治疗结局提供重大进展。

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.