Alpha Radioimmunotherapy for Lymphoma Treatment

描述(申请人提供)：抗CD20单抗(MAb)放射性标记的b-发射体可使65%-90%的非霍奇金淋巴瘤(NHL)患者在常规化疗失败时获得缓解。然而，使用这些单抗治疗的大多数患者随后复发。对于复发的非霍奇金淋巴瘤患者，造血细胞移植(HCT)是一种选择，但由于疾病复发，这种方法经常失败。由于大多数药物的非特异性，加强准备方案以减少复发一直受到毒性的限制。我们已经证明，肿瘤接受更高吸收剂量的辐射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，毒性是显著的，并不是所有的NHL患者都能通过靶向RIT策略结合HCT治愈。此外，CD20阴性的非霍奇金淋巴瘤患者，如T细胞非霍奇金淋巴瘤，不能从针对CD20抗原的靶向强化治疗中受益。放射性标记的抗CD45单抗作为骨髓细胞移植治疗复发性髓系疾病的预适应方案的一部分已经非常有效，但尚未在非霍奇金淋巴瘤的治疗方案中进行测试，尽管95%的非霍奇金淋巴瘤表达CD45抗原。我们最近已经开始探索131I-抗CD45单抗来改善在HCT环境下复发的NHL患者的预后，但毒性仍然很高，治愈率也不是最理想的。由于α发射体的短路径和高细胞毒性，α发射体在RIT中是一种有吸引力的替代γ发射体的方法。该项目的总体目标是通过使用？-发射体-Astatine-211(211At)将定向抗CD45放射治疗传递到患有自发性淋巴瘤的狗的疾病部位，以克服这些限制。我们预测，这种有效的治疗方案将根除微小残留病(MRD)，并以较低的毒性降低HCT后复发的风险。在目标1中，我们将定义最优反 CD45单抗在B细胞和T细胞NHL犬体内靶向CD45的蛋白剂量。我们预计，优化的抗CD45单抗剂量将靶向大部分表达CD45的细胞，同时保留正常组织。在目标2中，我们将使用在目标1中确定的最佳蛋白剂量来评估211At标记的抗CD45-单抗作为巩固治疗既往抗NHL化疗后缓解的犬的疗效和毒性。虽然这种方法有望消除MRD并提高缓解期犬的存活率，但治疗剂量的抗CD45 RIT治疗复发的NHL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单抗在NHL犬体内递增剂量和自体HCT治疗的可行性、安全性和有效性。最后，在目标4中，我们将通过进一步将这种方法推广到DLA相合和半相合的狗，评估用~(211)At标记的抗CD45单抗和同种异体HCT治疗NHL的RIT的相对优点。我们预计，来自这些研究的信息将允许使用211At-抗CD45单抗将优化的有前景的RIT策略快速转化为我们治疗NHL的临床RIT HCT计划。 公共卫生相关性：为淋巴瘤(或其他癌症)患者进行血液干细胞移植做准备所需的大剂量化疗或全身照射不能用于老年患者或有额外健康问题的患者。这项申请建议开发一种准备方案，将辐射主要传递给癌症，从而减少全身毒性。这些研究有可能为许多复发淋巴瘤患者的治疗结果提供重大进展。

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.