Development of Novel Therapies for Acute Lymphoblastic Leukemia

急性淋巴细胞白血病新疗法的开发

• 批准号: 10486999
• 负责人: Nirali Shah
• 金额: $ 87.61万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10486999
• 关键词: ABL1 gene; Acute Lymphocytic Leukemia; Acute leukemia; Address; Adolescent and Young Adult; Adoptive Cell Transfers; Age-Years; Allogenic; Anti-CD22; Antigen Targeting; Antigens; B lymphoid malignancy; B-Cell Leukemia; B-Lymphocytes; Binding; Biological; Bispecific Antibodies; Blood Component Removal; CAR T cell therapy; CD19 gene; CD22 gene; Cancer Etiology; Cells; Child; Childhood Acute Lymphocytic Leukemia; Clinic; Clinical; Clinical Oncology; Clinical Trials; Collaborations; Complex; Cytokine Receptors; Data; Development; Disease; Disease remission; Dose; Enrollment; FDA approved; Flow Cytometry; Foundations; Functional disorder; Future; Goals; Grant; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Immune response; Immunotherapeutic agent; Immunotherapy; Individual; Inflammatory Response; Infusion procedures; Journals; Lead; Malignant Childhood Neoplasm; Malignant Neoplasms; Manuscripts; Mediating; Minor; Modification; Outcome; Outcomes Research; Pathway interactions; Patient-Focused Outcomes; Patients; Pediatric Oncology; Ph+ ALL; Phenotype; Phosphotransferases; Play; Population; Production; Prognosis; Publishing; Quality of life; Recurrent disease; Refractory; Refractory Disease; Relapse; Remission Induction; Reporting; Research; Resistance; Risk; Role; Salvage Therapy; Signal Pathway; Surface Antigens; T cell response; T-Lymphocyte; TSLP gene; Testing; Thymus Gland; Toxic effect; Translations; Up-Regulation; Work; base; bench to bedside; chemotherapy; childhood cancer mortality; chimeric antigen receptor; chimeric antigen receptor T cells; clinically relevant; cohort; combinatorial; cytokine; density; disorder risk; early phase clinical trial; experience; familial hemophagocytic lymphohistiocytosis; first-in-human; follow-up; hematopoietic differentiation; high risk; immunoregulation; improved; improved outcome; leukemia; leukemia/lymphoma; mouse model; novel; novel therapeutics; overexpression; patient subsets; phase 1 study; phase I trial; pre-clinical; prevent; programs; promoter; receptor; receptor function; refractory cancer; resistance mechanism; response; targeted treatment; toxicity characteristics; treatment optimization; young adult

Overall summary: The most active efforts over the past several years have been directed to advancing CAR T-cell therapies. Based upon POB efforts in CD19 CAR T-cell and CD22 CAR T-cell trials, my team has taken a lead in the conduct of novel CAR T-cell based trials. This has provided the foundation for future iterations of CAR T-cell therapies, particularly as we move towards combinatorial targeting strategies and trials targeting novel antigens. CD22 CAR T-cells: Based on our experience to date, we are the first group to demonstrate clinical activity of CD22 CAR T-cells and have the largest experience to date. Our follow up manuscript describing our research outcomes was published in the Journal of Clinical Oncology in 2020 and we continue to explore how to further optimize this therapy. Our prior efforts in establishing a baseline for CD22 expression in children with r/r ALL, in collaboration with the NCI flow cytometry team, whose group is able to quantify antigen expression, were critical to understanding mechanisms of resistance to CD22 CAR. Indeed, the role of antigen expression density impacting effective CAR T-cell response first became clinically apparent in this trial. Through ongoing efforts, we have now enrolled and treated over 80 subjects on this trial, the majority of whom had received prior CD19-targeting. We have incorporated new scientific aims, opened new treatment cohorts, and implemented novel toxicity mitigating strategies, including those that address hemophagocytic lymphohistiocytosis (HLH)-like manifestations of CAR T-cell therapy. Importantly, we have identified unique aspects of CD22 CAR T-cell targeting that are distinct from those reported in CD19 targeting. We remain deeply invested in exploring the role of a minor manufacturing change on toxicity and are systematically exploring other attributes of CAR toxicity, which are particularly relevant as the field of targeted immunotherapies expands to improve outcomes for other types of refractory cancers and goes beyond CD19 targeting. Perhaps the greatest recognition of the impact of this work is FDA granting of "Breakthrough Therapy Designation" for our CD22 CAR T-cell construct (August 2019) and we are working to make this therapy more broadly available. The FDA breakthrough therapy designation is for the treatment of children and young adults, 3-30 years of age, with CD22+ B-cell ALL that is either refractory or in second or later relapse, and that is either CD19 negative or relapsed/refractory to CD19 targeting. This represents the first designation for an effective salvage therapy specifically for children and young adults who fail CD19 targeting and encompasses the goals of our section: to develop novel therapies for unmet needs. Based on the experiences with a clinically active CD22 CAR T-cell construct, we learned that targeting a different antigen on the same malignancy can have unique aspects on toxicity. Furthermore, in the context of this clinical trial, a single change was made to the upfront selection of the apheresis product prior to CAR T-cell manufacturing with no other downstream changes. Interestingly, this led to a heightened CAR-mediated inflammatory response necessitating a dose modification. Based on these two observations, along with the breakthrough therapy designation, current and future research efforts are focused on 1) Developing a pivotal CD22 CAR T-cell trial; 2) Enhancing the understanding of the pathophysiology that led to the unique characteristics of the toxicity profile of CD22 targeting and 3) Evaluating the impact of manufacturing on CAR T-cell responses. CD19/22 CAR: Due to the risk of antigen negative escape following single antigen targeted strategies and building upon our prior experiences with CD19 and CD22 targeting, a combinatorial CAR T-cell approach to prevent antigen negative relapse was developed in the Pediatric Oncology Branch. Utilizing a "bispecific" CAR approach to simultaneously target two antigens, the goal is to cover a broader range of the phenotypic variability in leukemia and avoid selection for a dim or negative population, with the ultimate goal to prevent antigen escape as a mechanism of relapse. This novel CAR construct was fully developed in the POB/NCI and tests the functionality of a simultaneous CD19/CD22 targeted approach for the treatment of patients who are both CD19 and CD22 positive. Notably, the two ScFv incorporated into this bispecific construct were derived from the active CD19 and CD22 CAR constructs that were both individually tested and confirmed to have efficacy as single antigen targeted CAR T-cells in the POB/NCI. This trial is now actively accruing, and a second version of a combinatorial construct is planned to go out into the clinic by early 2022. We have demonstrated both feasibility of manufacturing and a high response rate. Active efforts include understanding how different CAR T-cell promoters may impact CAR response, and how prior CAR T-cell therapy may impact future CAR T-cell options. TSLPR CAR T-cells: BCR-ABL1-like or Ph-like ALL is a high-risk subgroup of patients with ALL, defined by an activated kinase profile similar to that of BCR-ABL1- rearranged (Ph+) ALL, yet lacking the specific translocation. Thymic Stromal Lymphopoetin (TSLP) is a cytokine that plays a critical role in regulation of the immune response and in the differentiation of hematopoietic cells. It binds to the TSLP receptor (TSLPR), which is a heterodimeric complex encoded by Cytokine Receptor-Like Factor 2 (CRLF2), and IL-7ra subunit that when activated induces JAK/STAT pathway signaling. Recently published data indicate that when TSLPR is overexpressed, this pathway is associated with poor prognosis in high-risk disease, which makes TSLPR represents a promising target for future study. A novel TSLPR targeted CAR was developed in the Fry Lab. We are actively developing a phase I trial which we plan to bring to the clinic in 2022. This will be the first in human testing of anti-TSLPR CAR adoptive cell therapy. Antigen Modulation: Based on our work with CD22 CAR, we have demonstrated that cell surface antigen density is critical for the efficacy of CD22 CAR therapy and durability of remission. Bryostatin1 has been identified to increase CD22 expression and in a mouse model, when used as a "primer" before CD22 CAR, demonstrated enhanced cytokine production and improved CAR functionality, as well as a prolonged durability of remission, providing a proof of concept that increasing antigen expression optimizes CD22 CAR responses. Given the preclinical data which demonstrated that Bryostatin1-induced upregulation of CD22 in ALL may improve responsiveness to anti-CD22 targeted therapies, we are developing a phase 1 study to specifically test Bryostatin1 and its effects on CD22 expression in children and young adults with CD22+ leukemias.

总体总结：过去几年最积极的努力是推进 CAR T 细胞疗法。基于 POB 在 CD19 CAR T 细胞和 CD22 CAR T 细胞试验中所做的努力，我的团队率先开展了基于新型 CAR T 细胞的试验。这为 CAR T 细胞疗法的未来迭代奠定了基础，特别是当我们转向针对新抗原的组合靶向策略和试验时。 CD22 CAR T 细胞：根据我们迄今为止的经验，我们是第一个展示 CD22 CAR T 细胞临床活性的小组，并且拥有迄今为止最丰富的经验。我们描述我们研究成果的后续手稿已于 2020 年发表在《临床肿瘤学杂志》上，我们将继续探索如何进一步优化这种疗法。我们之前与 NCI 流式细胞术团队合作，建立了 r/r ALL 儿童 CD22 表达基线，该团队能够量化抗原表达，这对于了解 CD22 CAR 耐药机制至关重要。事实上，抗原表达密度对有效 CAR T 细胞反应的影响在该试验中首次在临床上变得明显。通过不断的努力，我们现已在该试验中招募并治疗了 80 多名受试者，其中大多数人之前接受过 CD19 靶向治疗。我们纳入了新的科学目标，开辟了新的治疗队列，并实施了新的毒性缓解策略，包括解决 CAR T 细胞疗法的噬血细胞淋巴组织细胞增多症 (HLH) 样表现的策略。重要的是，我们已经确定了 CD22 CAR T 细胞靶向的独特方面，与 CD19 靶向中报道的不同。我们仍然大力投入探索微小的制造变化对毒性的作用，并系统地探索 CAR 毒性的其他属性，随着靶向免疫治疗领域的扩展以改善其他类型难治性癌症的结果并超越 CD19 靶向，这些属性尤其重要。也许对这项工作影响的最大认可是 FDA 授予我们的 CD22 CAR T 细胞构建体“突破性疗法称号”（2019 年 8 月），我们正在努力使这种疗法得到更广泛的应用。 FDA 突破性疗法指定用于治疗 3-30 岁的儿童和年轻人，患有难治性或第二次或以后复发的 CD22+ B 细胞 ALL，并且 CD19 阴性或复发/难治性CD19 靶向。这代表了第一个专门针对 CD19 靶向失败的儿童和年轻人的有效挽救疗法的指定，并包含了我们部分的目标：针对未满足的需求开发新疗法。根据临床活性 CD22 CAR T 细胞构建体的经验，我们了解到针对同一恶性肿瘤的不同抗原可能会产生独特的毒性。此外，在本次临床试验中，在 CAR T 细胞制造之前对单采血液成分的前期选择进行了一次更改，没有其他下游更改。有趣的是，这导致 CAR 介导的炎症反应加剧，需要调整剂量。基于这两项观察结果，以及突破性疗法认定，当前和未来的研究工作重点关注：1) 开发关键的 CD22 CAR T 细胞试验； 2) 加强对导致 CD22 靶向毒性特征独特特征的病理生理学的理解，以及 3) 评估制造对 CAR T 细胞反应的影响。 CD19/22 CAR：由于单一抗原靶向策略存在抗原阴性逃逸的风险，并根据我们之前的 CD19 和 CD22 靶向经验，儿科肿瘤科开发了一种组合 CAR T 细胞方法来预防抗原阴性复发。利用“双特异性”CAR方法同时靶向两种抗原，目标是覆盖白血病更广泛的表型变异，并避免选择暗淡或阴性群体，最终目标是防止抗原逃逸作为复发机制。这种新型 CAR 结构在 POB/NCI 中得到充分开发，并测试了同时 CD19/CD22 靶向方法治疗 CD19 和 CD22 阳性患者的功能。值得注意的是，纳入该双特异性构建体的两个 ScFv 源自活性 CD19 和 CD22 CAR 构建体，它们均经过单独测试并确认在 POB/NCI 中具有作为单抗原靶向 CAR T 细胞的功效。该试验目前正在积极进行中，第二个版本的组合结构计划于 2022 年初进入临床。我们已经证明了制造的可行性和高响应率。积极的努力包括了解不同的 CAR T 细胞启动子如何影响 CAR 反应，以及先前的 CAR T 细胞治疗如何影响未来的 CAR T 细胞选择。 TSLPR CAR T 细胞：BCR-ABL1 样或 Ph 样 ALL 是 ALL 患者的高风险亚组，其定义为与 BCR-ABL1 重排 (Ph+) ALL 相似的激活激酶谱，但缺乏特定易位。胸腺基质淋巴细胞生成素 (TSLP) 是一种细胞因子，在调节免疫反应和造血细胞分化中发挥着关键作用。它与 TSLP 受体 (TSLPR) 结合，TSLPR 是由细胞因子受体样因子 2 (CRLF2) 和 IL-7ra 亚基编码的异二聚体复合物，激活后可诱导 JAK/STAT 通路信号传导。最近发表的数据表明，当 TSLPR 过度表达时，该通路与高危疾病的不良预后相关，这使得 TSLPR 成为未来研究的一个有希望的目标。 Fry 实验室开发了一种新型 TSLPR 靶向 CAR。我们正在积极开发一项 I 期试验，计划于 2022 年进入临床。这将是抗 TLPR CAR 过继细胞疗法的首次人体测试。抗原调节：基于我们对 CD22 CAR 的研究，我们证明细胞表面抗原密度对于 CD22 CAR 治疗的疗效和缓解的持久性至关重要。 Bryostatin1 已被确定可增加 CD22 表达，并且在小鼠模型中，当在 CD22 CAR 之前用作“引物”时，证明了细胞因子产生增强、CAR 功能改善以及缓解持续时间延长，这提供了概念证明：抗原表达优化 CD22 CAR 反应。鉴于临床前数据表明 Bryostatin1 诱导的 ALL 中 CD22 上调可能会改善抗 CD22 靶向治疗的反应性，我们正在开展一项 1 期研究，专门测试 Bryostatin1 及其对患有 CD22+ 白血病的儿童和年轻人中 CD22 表达的影响。