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: 10192681
• 负责人: Flavia Pichiorri
• 金额: $ 40.26万
• 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/10192681
• 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; 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.

尽管新药提高了多发性骨髓瘤 (MM) 患者的生存率，但癌细胞的能力 开发不同的治疗耐药机制为 使用克服这些机制的新方案。尽管 daratumumab 具有显着的抗 MM 活性 （达拉），越来越多的患者表现出具有更具侵袭性特征的复发性疾病。 尽管 CAR T 细胞疗法现在被认为是 Dara 复发患者为数不多的治疗选择之一， CAR T 细胞治疗后的复发（如多发性骨髓瘤和其他癌症中所见）也是一种不幸的情况。我们的 临床前数据表明，放射性抗体镥-177-Dara (177Lu-Dara) 可消除小鼠体内的 MM 细胞 患有系统性多发性骨髓瘤，但放射免疫疗法 (RIT) 的治疗剂量具有毒性，最终 致命。我们的数据还表明，尽管抗 CS1 CAR T 治疗的 MM 小鼠的生存期明显更长 与对照组相比，MM细胞没有被完全根除，并且动物会复发。因此，CS1 定向 CAR-T 疗法联合低剂量 CD38 定向 RIT 可能对治疗产生有益效果 复发的MM。为了检验这一假设，研究小组将确定最佳无毒有效 RIT 剂量作为 单一药物以及该剂量与 CAR T 细胞疗法联合使用时更有效的程度。这 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 CS1 CAR-T 细胞的剂量以及拟议疗法的时间安排和频率。到 驾驭这些无数的因素并提供最佳的治疗策略需要健全的 了解每种治疗方案所涉及的动态。在具体目标 1 中，抗 MM 剂量 Dara 导向的 RIT 将被优化，以实现最小化 BM 相关毒性。广泛的临床前研究 使用标记有两种临床相关放射性核素 177Lu 和 Actinium-225 的 DOTA-Dara 将在 MM 移植小鼠模型。具体目标2中，Dara RIT与CS1 CAR组合的抗肿瘤活性 将评估 T 细胞以实现以最小的 BM 毒性完全根除疾病。团队将进行 使用不同剂量和给药方式的放射性标记 Dara 和 CS1 CAR T 细胞进行体内组合研究 以便最大化 MM 杀伤活性和 T 细胞免疫激活。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 联合疗法的疗效。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 Dara 作为单一药物并与具有最小毒性的 CS1 CAR T 细胞组合。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 治疗急需新干预措施的患者的潜力。