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.

尽管新型药物增加了多发性骨髓瘤（MM）患者的存活率，但癌细胞的能力 为了发展对治疗治疗的耐药机制，已经为科学原理提供了 使用克服这些机制的新方案。尽管达拉特珠单抗具有明显的抗MM活性 （DARA），越来越多的患者表现出具有更具侵略性特征的复发性疾病。 尽管现在，CAR T细胞疗法被认为是Dara患者的少数治疗选择之一，但 如在MM和其他癌症中所见，汽车T细胞疗法后的复发也是一种不幸的情况。我们的 临床前数据表明，放射性抗体lutetium-177-dara（177lu-dara）消除了小鼠的MM细胞 轴承系统性MM疾病，但治愈剂量的放射免疫疗法（RIT）有毒，最终是有毒的 致命。我们的数据还表明，尽管抗CS1 CAR T处理的MM小鼠的存活率明显更长 与对照组相比，MM细胞未完全消除，动物复发。因此，CS1 定向的CAR-T治疗与较低剂量CD38定向RIT结合使用可能对治疗有益 复发毫米。为了检验这一假设，团队将确定最佳无毒有效RIT剂量 与CAR T细胞疗法结合使用时，单药和该剂量的程度更有效。这 治疗的功效取决于多种因素，例如疾病负担，骨髓（BM）毒性， RIT剂量，抗CS1 CAR-T细胞的剂量以及拟议疗法的调度和频率。到 浏览这些无数因素并提供最佳的治疗策略需要声音 了解每种治疗选择中涉及的动态。在特定目标1中，抗MM剂量 DARA定向的RIT将被优化，以实现最小的BM相关毒性。广泛的临床前研究 使用两个临床相关放射性核素标记的dota-dara将在177lu和actinium-225中进行 MM促进的小鼠模型。在特定的目标2中，将DARA RIT和CS1 CAR的抗肿瘤活性 将对T细胞进行评估，以最小的BM毒性实现完全消除的疾病。团队将进行 使用放射性标记的DARA和CS1 CAR T细胞以不同剂量和给药的体内组合研究 为了最大程度地提高MM杀伤活性和T细胞免疫激活。在特定目标3中，小组 将开发一个数学模型来预测RIT和CS1 CAR-T治疗的疗效。 dara- 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 和普通的基于微分方程的模型。开发的建模框架将用于研究和 预测不同治疗组合的结果。这些研究将定义最佳治疗剂量 放射性标记的DARA作为单一药物，并与CS1 CAR T细胞结合使用，具有最小的毒性。因为 DARA的患者保持CS1和CD38的表达，据信我们的治疗方法具有 治疗高度需要新干预的患者的潜力。