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

探索治疗性放射性标记达雷木单抗（抗 CD38）与抗 CS1 CAR T 细胞联合作为多发性骨髓瘤新型组合治疗的临床前相关性

• 批准号: 10463647
• 负责人: Flavia Pichiorri
• 金额: $ 39.45万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10463647
• 关键词: Actinium; Animals; Antibodies; Bone Marrow; CAR T cell therapy; Cell surface; Cells; Clinic; Clinical; Control Groups; Data; Differential Equation; Disease; Dose; Epitopes; Exhibits; FDA approved; Frequencies; Health; Hematopoietic Neoplasms; Human; IgG1; Image; Immune; ImmunoPET; Immunologist; Intervention; Label; Laboratories; Lutetium; Malignant Neoplasms; Mathematics; Medical; Modeling; Multiple Myeloma; Mus; New Agents; Patients; Phase; Plasma Cells; Positioning Attribute; Publishing; Radioactive; Radioimmunotherapy; Radioisotopes; Radiolabeled; Receptor Cell; Recurrent disease; Regimen; Relapse; Reporting; Resistance; Schedule; Scientist; Surface; Survival Rate; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Translating; Treatment Efficacy; Work; base; burden of illness; cancer cell; chimeric antigen receptor; chimeric antigen receptor T cells; clinically relevant; combinatorial; diagnostic criteria; experience; humanized antibody; immune activation; immunoengineering; in vivo; mathematical model; mouse model; novel; novel therapeutic intervention; outcome prediction; personalized diagnostics; pre-clinical; preclinical study; radiotracer; relapse patients; resistance mechanism; sound; targeted treatment; therapeutic target; treatment optimization

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.

虽然新型药物增加了多发性骨髓瘤（MM）患者的生存率，但癌细胞的能力 对治疗性治疗产生不同的耐药性机制，为以下研究提供了科学依据： 使用能克服这些机制的新疗法。尽管达雷妥尤单抗具有显著的抗MM活性 （达拉），越来越多的患者表现出具有更侵袭性特征的复发性疾病。 虽然CAR T细胞疗法现在被认为是Dara复发患者的少数治疗选择之一， CAR T细胞治疗后的复发，如MM和其他癌症中所见，也是一种不幸的情况。我们 临床前数据显示放射性抗体镥-177-达拉（177 Lu-达拉）消除小鼠中的MM细胞 患有全身性MM疾病，但放射免疫疗法（RIT）的治疗剂量是有毒的， 致命的我们的数据还表明，尽管抗CS 1 CAR T治疗的MM小鼠具有显著更长的存活时间， 与对照组相比，MM细胞没有被完全根除，并且动物复发。因此，CS 1 定向CAR-T疗法联合低剂量CD 38定向RIT可能在治疗中具有有益作用。 为了检验这一假设，研究小组将确定最佳无毒有效RIT剂量， 单一药剂以及当与CAR T细胞疗法组合时该剂量更有效的程度。的 治疗效果取决于多种因素，例如疾病负担，骨髓（BM）毒性， RIT的剂量、抗CS 1 CAR-T细胞的剂量以及拟定疗法的时间表和频率。到 通过这些无数的因素导航并提供最佳的治疗策略需要一个健全的 了解每种治疗方案所涉及的动力学。在具体目标1中，抗MM剂量 将优化Dara定向RIT的剂量以实现最小的BM相关毒性。广泛的临床前研究 使用DOTA-Dara标记两种临床相关放射性核素177 Lu和Actinium-225，将在 MM移植小鼠模型。在具体目标2中，组合达拉RIT和CS 1 CAR的抗肿瘤活性 将评价T细胞以实现完全疾病根除，同时具有最小的BM毒性。该小组将进行 使用不同剂量和给药的放射性标记的达拉和CS 1 CAR T细胞的体内组合研究 时间表，以最大化MM杀伤活性和T细胞免疫活化。在具体目标3中，小组 将开发一个数学模型来预测RIT和CS 1 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参数化放射生物学 和基于常微分方程的模型。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 放射性标记的达拉作为单一药剂和与CS 1 CAR T细胞组合，具有最小的毒性。因为 Dara复发患者维持CS 1和CD 38的表达，相信我们的治疗方法具有良好的疗效。 治疗高度需要新型干预措施的患者的潜力。