preclinical optimization of BCMA directed T cell therapy

项目摘要 多发性骨髓瘤（MM）治疗的支柱是DNA烷化剂（环磷酰胺，美法仑），蛋白酶体 抑制剂（硼替佐米、卡非佐米、ixazomib）、糖皮质激素（地塞米松、泼尼松）和IMiD （沙利度胺、来那度胺、泊马度胺）。尽管取得了初步的反应，患者不可避免地复发 MM仍然无法治愈。最近，免疫疗法获得了显着的反应： 抗CD 38抗体（达雷妥尤单抗）、抗BCMA双特异性抗体或BiTE、抗BCMA CAR-T细胞。 然而，与常规疗法所观察到的类似，这些免疫肿瘤剂中没有一种是有效的。 有疗效的我们认为，为了改善患者的预后，我们需要更好地定义 肿瘤对周围免疫细胞的影响以及常规和免疫疗法对肿瘤细胞的影响。 肿瘤及其微环境不幸的是，大多数临床前研究都是在异种移植模型上进行的 缺乏免疫系统，或用人类免疫亚群瞬时重建，并且未能捕获 肿瘤和免疫细胞之间复杂的相互作用。 使用我们已经产生的具有临床预测性的、完全免疫活性的MM Vk*MYChCRBN小鼠模型， 我们发现对抗BCMA双特异性抗体的敏感性受高肿瘤负荷的影响， 过度的抗原刺激和T细胞耗竭。联合疗法旨在增强T细胞功能 增加双特异性抗体的短期活性，但小鼠最终复发， 总体生存率。令人惊讶的是，环磷酰胺的加入被证明是非常有效的， 但持续的T细胞活化在一小部分小鼠中是治愈性的。 根据我们在VkMYChCRBN MM中的结果，我们设计了一项I期、随机化II期临床试验， BCMA/CD 3双特异性抗体teclistamab与添加的伊贝多胺或环磷酰胺。在这 我们的建议旨在使用单药teclistamab或联合治疗MM患者的结果 用伊贝多胺或环磷酰胺来证明Vk*MYChCRBN MM模型用于T细胞定向的 免疫疗法最后，我们将研究调节免疫保护发展的因素。 并在双特异性抗体治疗后治愈。总体而言，这些数据将进一步证明Vk*MYChCRBN小鼠 MM的模型，并为MM双特异性抗体的临床开发提供信息。

PROJECT SUMMARY The pillars of multiple myeloma (MM) therapy are DNA alkylators (cyclophosphamide, melphalan), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), glucocorticoids (dexamethasone, prednisone) and IMiDs (thalidomide, lenalidomide, pomalidomide). Despite achieving an initial response, patients inevitably relapse and MM remains incurable. More recently, remarkable responses have been obtained with immunotherapy: antibodies against CD38 (daratumumab), bi-specific antibodies or BiTEs to BCMA, CAR-T cells against BCMA. However, similarly to what observed with conventional therapy, none of these immune-oncology agents are curative. We believe that in order to improve patient outcome we need to better define the changes induced by the tumor on the surrounding immune cells and the effects that conventional and immunotherapy exert on the tumor and its microenvironment. Unfortunately, most preclinical studies are conducted on xenograft models lacking an immune system, or transiently reconstituted with human immune subsets and fail to capture the complex interaction between tumor and immune cells. Using the clinically predictive, fully immunocompetent Vk*MYChCRBN mouse model of MM we have generated, we discovered that sensitivity to anti-BCMA bispecific antibody is affected by high tumor burden, which drives excessive antigenic stimulation and T cell exhaustion. Combination therapies aimed to boost T cell function increase the short-term activity of the bispecific antibody, but mice eventually relapse with modest improve in overall survival. Surprisingly, the addition of cyclophosphamide proved very effective, by inducing a tempered but durative T cell activation which was curative in a fraction of mice. Based on our results in VkMYChCRBN MM we have designed a phase 1, randomized phase 2 clinical trial of a BCMA/CD3 bispecific antibody teclistamab with the addition either iberdomide or cyclophosphamide. In this proposal we aim to use the results of treating MM patients with either single agent teclistamab, or combinations with iberdomide or cyclophosphamide to credential the Vk*MYChCRBN MM model for T-cell directed immunotherapy. Finally, we will investigate factors that regulate the development of immunologic protection and cure after bispecific antibody therapy. Overall, these data will further credential the Vk*MYChCRBN mouse model of MM and inform the clinical development of bispecific antibodies in MM.