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.

总结总结：过去几年中，最积极的努力是针对推进T细胞疗法的。基于CD19 CAR T-Cell和CD22 CAR T细胞试验的POB努力，我的团队在基于新型CAR T细胞试验的行为中领先。这为未来的汽车T细胞疗法迭代奠定了基础，尤其是当我们朝着针对新型抗原的组合靶向策略和试验迈进时。 CD22 CAR T细胞：根据迄今为止我们的经验，我们是第一个展示CD22 CAR T细胞临床活动并拥有最大经验的临床活动。我们描述我们的研究结果的后续手稿发表在2020年的《临床肿瘤学杂志》上，我们继续探索如何进一步优化这种疗法。我们先前与NCI流式细胞仪小组合作建立R/R儿童中CD22表达的基线的努力，他们的组能够量化抗原表达，对于理解CD22 CAR耐药性的机制至关重要。实际上，在该试验中，抗原表达密度影响有效的汽车T细胞反应的作用首先在临床上显而易见。通过正在进行的努力，我们现在已经入学并接受了80多名受试者，其中大多数人都接受过CD19靶向。我们已经结合了新的科学目的，开设了新的治疗队列并实施了新型毒性降低策略，包括那些针对造血细胞淋巴淋巴细胞增多症（HLH）类似CAR T细胞疗法的表现的毒性。重要的是，我们已经确定了CD22 CAR T细胞靶向的独特方面，这些方面与CD19靶向中报告的靶向不同。我们在探索毒性中的微小制造变化的作用方面仍然深入投入，并系统地探索了汽车毒性的其他属性，随着目标免疫疗法领域的扩展，这些属性特别相关，以改善其他类型的难治性癌症的成果，并且超越了CD19的目标。也许对这项工作的影响的最大认可是FDA授予我们的CD22汽车T细胞结构的“突破疗法名称”（2019年8月），我们正在努力使该疗法更广泛地可用。 FDA突破性疗法指定是用于3-30岁的儿童和年轻人的治疗，CD22+ B-cell所有这些都是难治性的或第二或更高版本的复发，这是CD19阴性或复发/对CD19靶向的复发/难治性。这代表了专门针对CD19靶向CD19的儿童和年轻人进行有效的打捞疗法的首次指定，并涵盖了我们部分的目标：为未满足的需求开发新的疗法。根据临床活跃的CD22 CAR T细胞构建体的经验，我们了解到，将不同的抗原靶向相同的恶性肿瘤可以在毒性上具有独特的方面。此外，在这项临床试验的背景下，在没有其他下游变化的情况下，在进行T-Cell制造之前对寄托学产品的前期选择进行了单一的变化。有趣的是，这导致CAR介导的炎症反应加剧，需要进行剂量修饰。基于这两个观察结果，以及突破性疗法的指定，当前和未来的研究工作集中在1）开发关键的CD22 CAR T细胞试验； 2）增强对导致CD22靶向毒性特征的独特特征的病理生理学的理解和3）评估制造对汽车T细胞反应的影响。 CD19/22 CAR：由于单个抗原靶向策略的抗原阴性逃逸风险，并基于我们先前使用CD19和CD22靶向的经验，因此在儿科肿瘤学分支中发展了一种防止抗原阴性复发的组合CAR T细胞方法。利用“双特异性”汽车方法同时靶向两种抗原，目标是覆盖白血病中更广泛的表型变异性，并避免选择昏暗或负人的人群，以防止抗原逃脱作为复发机制。这种新型的汽车构建体已在POB/NCI中充分开发，并测试了同时CD19/CD22靶向方法的功能，用于治疗CD19和CD22阳性的患者。值得注意的是，该双特异性构建体中的两个SCFV源自活动的CD19和CD22 CAR构建体，它们均已单独测试并确认为POB/NCI中的单个抗原靶向CAR T细胞具有功效。该试验现在正在积极地进行，并且计划在2022年初到2022年初进入诊所。我们已经证明了制造业的可行性和高响应率。积极的努力包括了解不同的汽车T细胞启动子如何影响汽车反应，以及先前的T细胞疗法如何影响未来的T-Cell选项。 TSLPR CAR T细胞：BCR-ABL1样或类似pH的TSLS是所有患者的高风险亚组，由活化的激酶谱类似于BCR-ABL1-重新排列（pH+）的激活激酶谱，但缺乏特定的易位。胸腺基质淋巴蛋白（TSLP）是一种细胞因子，在调节免疫反应和造血细胞的分化中起着至关重要的作用。它与TSLP受体（TSLPR）结合，该受体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，当激活时会诱导JAK/Stat STAT途径信号传导。最近发布的数据表明，当TSLPR过表达时，该途径与高风险疾病的预后不良有关，这使TSLPR代表了未来研究的有希望的目标。在Fry Lab中开发了一种新型的TSLPR靶向汽车。我们正在积极开发一项I期试验，该试验计划在2022年将其带到诊所。这将是对抗TSLPR CAR养细胞疗法进行人体测试的首次测试。抗原调节：根据我们使用CD22 CAR的工作，我们证明了细胞表面抗原密度对于CD22 CAR治疗和缓解耐用性至关重要。 Bryostatin1已被鉴定为增加CD22的表达，而在小鼠模型中，当用作CD22 CAR之前的“底漆”时，证明了细胞因子的产生增强和改善的CAR功能，以及延长的缓解耐用性，提供了概念的证明，从而增加了抗原表达的抗原表达功能，可以使CD22 CAR的响应功能增强。鉴于临床前数据表明，Bryostatin1诱导的CD22的上调在所有人中都可能提高对抗CD22靶向疗法的反应性，我们正在开发一项1期研究，以特别测试Bryostatin1及其对CD22+白血病儿童和年轻人的CD22表达的影响。