BCMA Specific Chimeric Antigen Receptor (CAR)-T Cells for Treatment of Patients with Multiple Myeloma

项目总结 项目2 目前美国有12万名多发性骨髓瘤(MM)患者，其中绝大多数 将死于他们的疾病，尽管对最近引入的抗MM药物的初始应答率很高。集约化 化疗后进行自体干细胞移植(ASCT)可增加完全缓解(CR)率 并延长生存时间。尽管如此，多发性骨髓瘤仍然是无法治愈的，每一种疾病的顺序治疗都是不可避免的 复发导致反应持续时间逐渐缩短，这是由于MM细胞对 可用的治疗方法。最终，几乎所有的患者都会出现治疗反应迟缓的多发性骨髓瘤，从而导致死亡 每年超过11,000名美国人。免疫疗法，使用针对肿瘤相关分子的抗体， 免疫检查点，或肿瘤反应性T细胞的过继转移，已成为一种有效的方式 对于许多癌症，包括MM。通过基因转移工程的T细胞进行过继细胞治疗，以表达 合成嵌合抗原受体(CARS)是MM-CAR-T的一种潜在的变革性方法 细胞不受人类白细胞抗原的限制，不像T细胞受体定向治疗，可以治疗所有患有 表达汽车识别的表面分子。该项目将探索设计和优化的汽车 B细胞成熟抗原(BCMA)是一种表达在MM上的跨膜受体，具有特异性。 这些汽车包含新的特征，改善了功能，实现了体内跟踪，并促进了CAR-T细胞 制造业。表达我们优化的BCMA Cars的T细胞在体外和体内都能有效地对抗MM 临床前模型。该项目(项目2)是这笔赠款的新方向，提出了一项自体移植的临床试验。 用含有不同共刺激结构域的BCMA CARS转导的T细胞，并以统一的T细胞 MM患者的细胞亚群组成。这些研究将确定在 表达CD28/CD3的CAR-T细胞的毒性和功能还是4-1BB/CD3？信令域，以及 确定肿瘤细胞对ACT耐药的内在和外在机制。世界银行的一个焦点 建议制定策略，克服对ACT的耐药性，并获得更高的 完全缓解。我们已经确定BCMA的低表达是T细胞的潜在屏障 MM的识别，临床前数据表明可以采取措施增加表面BCMA 在MM上，同时降低可溶性BCMA水平。来那度胺(LEN)是阿司匹林的重要成分 MM疗法和临床前研究被提出来检验LEN对CAR-T细胞的影响 支持未来CAR--T细胞组合的临床试验。总体而言，项目2将决定安全性 以及每种CAR结构的有效性，并增强了对共刺激信号如何 影响CAR-T细胞的命运和功能，同时使用临床前模型来前瞻性地解决 CAR-T细胞效能的潜在障碍。这些发现将为未来的临床试验提供信息，并推动 采用细胞疗法。

PROJECT SUMMARY PROJECT 2 There are currently 120,000 patients in the United States living with multiple myeloma (MM) and a vast majority will die of their disease despite high initial rates of response to recently introduced anti-MM agents. Intensive chemotherapy followed by autologous stem cell transplant (ASCT) can increase complete remission (CR) rates and prolong survival. Nonetheless, MM remains incurable and sequential lines of treatment for each inevitable relapse results in progressively shorter durations of response due to acquired resistance by MM cells to available therapy. Ultimately, almost all patients develop treatment unresponsive MM, which leads to the death of over 11,000 Americans annually. Immunotherapy, using antibodies specific for tumor associated molecules, immune checkpoints, or the adoptive transfer of tumor reactive T cells, has emerged as an effective modality for many cancers, including MM. Adoptive cell therapy with T cells engineered by gene transfer to express synthetic chimeric antigen receptors (CARs) represents a potentially transformative approach for MM. CAR-T cells are not HLA-restricted and unlike T cell receptor directed therapy, can treat all patients with tumors that express the surface molecule recognized by the CAR. This project will explore CARs designed and optimized with specificity for B cell maturation antigen (BCMA) a transmembrane receptor that is expressed on MM. These CARs contain novel features that improve function, enable in vivo tracking, and facilitate CAR-T cell manufacturing. T cells expressing our optimized BCMA CARs are effective against MM in vitro and in preclinical models. This Project (Project 2), a new direction on this grant, proposes a clinical trial of autologous T cells transduced with BCMA CARs containing different costimulatory domains and formulated in a uniform T cell subset composition for patients with MM. The studies will determine whether there are differences in toxicity and function of CAR-T cells expressing CD28/CD3? or 4-1BB/CD3? signaling domains, and identify tumor cell intrinsic and extrinsic mechanisms of MM resistance to ACT. A focus of the proposal is to develop strategies to overcome resistance to ACT and obtain a higher rate of complete remission. We have identified low BCMA expression as a potential barrier to T cell recognition of MM, and preclinical data shows that measures can be taken to increase surface BCMA on MM, while decreasing soluble BCMA levels. Lenalidomide (Len) is a critical component of current MM therapy and preclinical studies are proposed to examine the effects of Len on CAR--T cells to support future clinical trials of CAR--T cells in combination. Overall, Project 2 will determine the safety and efficacy of each of the CAR constructs, and enhance the understanding of how costimulatory signaling affects the fate and function of CAR-T cells while employing preclinical models to prospectively address potential barriers to CAR-T cell efficacy. Findings will inform future clinical trials and advance the field of adoptive cell therapy.