Project 3: Combinatorial and gene-editing approaches to enhance the efficacy of CAR T cell therapy of multiple myeloma.

项目 3：组合和基因编辑方法增强 CAR T 细胞治疗多发性骨髓瘤的疗效。

• 批准号: 10245065
• 负责人: EDWARD A STADTMAUER
• 金额: $ 56.7万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10245065
• 关键词: Adoptive Immunotherapy; Antibodies; Antigen Targeting; Antigens; B lymphoid malignancy; B-Lymphocytes; Biological Assay; Biological Markers; Biology; Bone Marrow; CAR T cell therapy; CD19 Antigens; CD19 gene; Cell Maturation; Cell Therapy; Cells; Cellular Structures; Cellular immunotherapy; Cessation of life; Clinical; Clinical Research; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Disease; Environment; Evaluation; Exhibits; Favorable Clinical Outcome; Frequencies; Future; Genes; Hematologic Neoplasms; Immune Evasion; Immunophenotyping; Immunotherapy; In Vitro; Knock-out; Knowledge; Ligands; Malignant - descriptor; Malignant Neoplasms; Marrow; Measures; Mediating; Mission; Modeling; Modernization; Modification; Multiple Myeloma; Neoplastic Plasma Cell; Outcome; Patient-Focused Outcomes; Patients; Phenotype; Plasma Cells; Population; Predisposition; Public Health; Research; Resistance; Role; Safety; Sampling; T-Lymphocyte; Test Result; Testing; Therapeutic; Translating; Treatment Failure; Up-Regulation; Work; base; cancer cell; chimeric antigen receptor; chimeric antigen receptor T cells; combinatorial; design; immune checkpoint; improved; improved outcome; innovation; neoplastic cell; novel; novel therapeutic intervention; pre-clinical; precursor cell; primary endpoint; programmed cell death ligand 1; programmed cell death protein 1; recoverin protein; resistance mechanism; response; safety and feasibility; safety testing; stem cells; tumor; tumor microenvironment

SUMMARY (PROJECT 3) Recent therapeutic advances have led to incremental improvement in response rates and survival in multiple myeloma. Unfortunately, the disease remains mostly incurable. Anti-CD19 chimeric antigen receptor redirected T cells have been particularly successful in other B-cell malignancies; CD19 is rarely expressed on the malignant plasma cell, though CD19 may be present on rare putative myeloma precursor cells. The B Cell Maturation Antigen, BCMA, is commonly present on neoplastic plasma cells but may not be on the earliest precursors or resistant clones. In patients with advanced multiple myeloma we have observed potent anti- myeloma responses with CAR T cells directed against BCMA (BCMA-CAR) and prolonged responses after CTL019. The depth and durability of these responses are promising, but have varied, and not all patients have had clinical benefit. Treatment failures have been observed in CD19 expressing malignancies such as ALL, CLL and NHL and a number of resistance mechanisms have been observed. In this Project we seek to determine the particular resistance mechanisms that limit CAR T cell therapy for myeloma and develop strategies to overcome them. This will be accomplished in three specific aims. In Aim 1 the frequency and functional clonogenicity of clonotypic B cells will be determined from samples derived from patients treated with CTL019 and BCMA-CAR and correlated with clinical outcome. In Aim 2, we seek to target both early precursors and more differentiated malignant cells to completely eliminate the malignant clone. The feasibility and safety of combining CTL019 and BCMA-CAR will be tested in a clinical trial of patients with advanced myeloma. The degree of depletion of malignant clones and comparison of these clinical results to monotherapy will be assessed. The combined results of Aim 1 and 2 will guide future trials of dual-CAR therapy. In Aim 3 we seek to invent a better anti-myeloma CAR T cell. Detailed immunophenotyping and functional assays of CAR T cells and the tumor environment from samples derived from patients treated on the CAR T trials will be made. These studies will guide the construction of new BCMA-CARs that utilize CRISPR gene-editing to knock-out the most relevant immune checkpoint molecules. This research will be significant because it is aimed at eliminating the myeloma cell of origin and be potentially curative. The innovation of the proposed research lies not just in targeting an antigen commonly on the tumor cell (BCMA) but in addition targeting a second antigen (CD19) on the malignant precursors. The knowledge gained by this project will advance the cellular immunotherapy field.

概要（项目3） 最近的治疗进展已经导致多个肿瘤的反应率和生存率的逐步改善。 骨髓瘤不幸的是，这种疾病大多无法治愈。抗CD 19嵌合抗原受体重定向 T细胞在其他B细胞恶性肿瘤中特别成功; CD 19很少表达在T细胞上。 恶性浆细胞，尽管CD 19可能存在于罕见的推定骨髓瘤前体细胞上。B细胞 成熟抗原，BCMA，通常存在于肿瘤性浆细胞上，但可能不是最早出现在肿瘤性浆细胞上。 前体或抗性克隆。在晚期多发性骨髓瘤患者中，我们观察到有效的抗- 使用针对BCMA的CAR T细胞（BCMA-CAR）的骨髓瘤应答和在治疗后的延长应答 CTL019。这些反应的深度和持久性是有希望的，但有变化，并不是所有的患者都有 有临床效益。在表达CD 19的恶性肿瘤如ALL中观察到治疗失败， 已观察到CLL和NHL以及许多耐药机制。在本项目中，我们力求 确定限制CAR T细胞治疗骨髓瘤的特定耐药机制， 战略来克服它们。这将通过三个具体目标来实现。在目标1中， 克隆型B细胞的功能性克隆形成性将从来源于用以下药物治疗的患者的样品中测定： CTL 019和BCMA-CAR与临床结果相关。在目标2中，我们寻求尽早实现这两个目标 前体和更分化的恶性细胞，以完全消除恶性克隆。可行性 联合使用CTL 019和BCMA-CAR的安全性将在晚期乳腺癌患者的临床试验中进行测试。 骨髓瘤恶性克隆的耗竭程度以及这些临床结果与单药治疗的比较 将予以评估。目标1和目标2的综合结果将指导未来的双CAR治疗试验。在目标3中， 寻求发明更好的抗骨髓瘤CAR T细胞。CAR T的详细免疫表型和功能测定 细胞和肿瘤环境的样本来源于在CAR T试验中治疗的患者。 这些研究将指导新BCMA-CAR的构建，这些新BCMA-CAR利用CRISPR基因编辑来敲除 最相关的免疫检查点分子。这项研究将是重要的，因为它旨在 消除起源的骨髓瘤细胞并具有潜在的治愈性。本研究的创新之处在于 不仅靶向肿瘤细胞（BCMA）上常见的抗原， （CD 19）的恶性前体。这个项目所获得的知识将促进细胞 免疫治疗领域。