Exploring the preclinical relevance of therapeutic radiolabeled daratumumab (anti-CD38) in combination with anti-CS1 CAR T cells as a novel combinatorial treatment for multiple myeloma

尽管新的药物已经提高了多发性骨髓瘤(MM)患者的存活率，但癌细胞的能力 发展不同的耐药机制为治疗提供了科学依据 使用克服这些机制的新养生法。尽管Daratumumab具有显著的抗MM活性 (DARA)，越来越多的患者表现出复发的疾病，具有更具侵袭性的特征。 尽管CAR T细胞疗法现在被认为是为数不多的DARA复发患者的治疗选择之一， 在多发性骨髓瘤和其他癌症中看到的CAR T细胞治疗后复发也是一种不幸的情况。我们的 临床前数据显示，放射性抗体Lu-177-Dara(177Lu-Dara)可消除小鼠的MM细胞 患有系统性多发性骨髓瘤，但放射免疫治疗(RIT)的治疗剂量是有毒的，并最终 致命的。我们的数据还表明，尽管抗CS1 CAR T处理的MM小鼠的存活时间明显延长 与对照组相比，MM细胞并未完全根除，动物复发。因此，CS1 定向CAR-T疗法联合小剂量CD38定向RIT治疗可能具有良好的疗效 为了检验这一假设，研究小组将确定最佳无毒有效RIT剂量为 以及当与CAR T细胞治疗联合使用时，该剂量更有效的程度。这个 治疗的效果取决于多种因素，如疾病负担、骨髓毒性、 RIT的剂量，抗CS1 CAR-T细胞的剂量，以及拟议治疗的时间安排和频率。至 驾驭这些无数因素并提供最佳治疗策略需要健全的 了解每一种治疗方案所涉及的动态。在特定目标1中，抗多发性骨髓瘤剂量 DARA导向的RIT的毒性将被优化，以实现最小的BM相关毒性。广泛的临床前研究 使用标记了两种临床相关放射性核素177Lu和Actdium-225的DOTA-DARA将在#年进行 移植MM的小鼠模型。靶向2：Dara-RIT与CS1-CAR的联合抗肿瘤活性 将对T细胞进行评估，以实现完全根除疾病，并将骨髓毒性降至最低。该团队将进行 放射性标记的DARA和CS1CAR T细胞在不同剂量和给药下的体内组合研究 计划，以最大限度地发挥MM杀伤活性和T细胞免疫活性。在具体目标3中，小组 将开发一个数学模型来预测RIT和CS1 CAR-T联合治疗的疗效。达拉- 定向RIT优化研究和体内组合研究将用于放射生物学的参数化 和基于常微分方程式的模型。开发的建模框架将用于研究和 预测不同治疗组合的结果。这些研究将确定最佳治疗剂量 将放射性标记的DARA作为单一试剂，与CS1 CAR T细胞联合使用，毒性最小。因为 DARA复发患者维持CS1和CD38的表达，相信我们的治疗方法已经 治疗迫切需要新干预措施的患者的潜力。

Although novel agents have increased the survival of multiple myeloma (MM) patients, the ability of cancer cells to develop different mechanisms of resistance to therapeutic treatments has provided the scientific rationale to use new regimens that overcome these mechanisms. Despite the significant anti-MM activity of daratumumab (Dara), an increasing number of patients have exhibited relapsing disease with more aggressive features. Although CAR T cell therapy is now considered one of few therapeutic options for Dara-relapsing patients, relapse after CAR T cell therapy, as seen in MM and other cancers, is also an unfortunate scenario. Our preclinical data show that the radioactive antibody lutetium-177-Dara (177Lu-Dara) eliminates MM cells in mice bearing systemic MM disease, but that the curative doses of radioimmunotherapy (RIT) are toxic and eventually lethal. Our data also show that, although the anti-CS1 CAR T-treated MM mice have a significantly longer survival compared to control groups, MM cells are not completely eradicated, and the animals relapse. Thus, CS1 directed CAR-T therapy combined with lower dose CD38-directed RIT may have a beneficial effect in treating relapsing MM. To test this hypothesis, the team will determine the optimal non-toxic effective RIT dose as a single agent and the extent to which this dose is more effective when combined with CAR T cell therapy. The efficacy of treatment depends on a multitude of factors such as the disease burden, bone marrow (BM) toxicity, dose of RIT, dose of anti-CS1 CAR-T cells, and the scheduling and the frequency of the proposed therapies. To navigate through these myriad factors and deliver an optimal therapeutic strategy requires a sound understanding of the dynamics involved in each of the therapeutic options. In Specific Aim 1, the anti-MM dose of Dara-directed RIT will be optimized to achieve minimal BM associated toxicity. Extensive preclinical studies using DOTA-Dara labeled with two clinical relevant radionuclides, 177Lu and Actinium-225, will be conducted in an MM-engrafted mouse model. In Specific Aim 2, the antitumor activity of combining Dara RIT and CS1 CAR T cells will be evaluated to achieve complete disease eradication with minimal BM toxicity. The team will conduct in vivo combinatorial studies using radiolabeled Dara and CS1 CAR T cells at different doses and administration schedules in order to maximize MM killing activity and T cell immune activation. In Specific Aim 3, the group will develop a mathematical model to predict the efficacy of combined RIT and CS1 CAR-T therapy. Dara- directed RIT optimization studies and in vivo combinatorial studies will be used to parameterize radiobiological and ordinary differential equation based models. The developed modeling framework will be use to study and predict outcomes of different therapeutic combinations. These studies will define the optimum therapeutic dose of radiolabeled Dara as a single agent and in combination with CS1 CAR T cells with minimal toxicity. Because Dara-relapsing patients maintain expression of CS1 and CD38, it is believed that our therapeutic approach has the potential to treat patients for which novel interventions are highly needed.