BAFF-R CAR T cell therapy for ALL

BAFF-R CAR T 细胞疗法治疗 ALL

基本信息

批准号：
10610931
负责人：
IBRAHIM ALDOSS
金额：
$ 66.41万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-18 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610931
关键词：
Acute Address Adult Affect Aftercare Alternative Therapies Antigen Receptors Antigens Autoimmune Diseases B lymphoid malignancy B-Cell Acute Lymphoblastic Leukemia B-Cell Neoplasm B-Lymphocytes CAR T cell therapy CD19 Antigens CD19 gene CD22 gene Cell Survival Cell physiology Child Childhood Cities Clinical Clinical Trials Correlative Study Cyclic GMP Data Data Analyses Development Disease Dose Down-Regulation Enrollment Epitopes FDA approved Failure Fc Receptor Generations Genetic Engineering Hematologic Neoplasms Human Engineering Immune Immunotherapy In Vitro Interleukin 4 Receptor Kinetics Laboratory Research Lentivirus Ligands Lymphoblastic lymphoma Lymphoid Cell Lymphoma Lymphoma cell Manuscripts Modeling Monoclonal Antibodies Multiple Myeloma NK cell therapy Outcome Patient Care Patient-Focused Outcomes Patients Phase Phenotype Population Preparation Principal Investigator Prognosis Property Recommendation Recurrent disease Refractory Relapse Remission Induction Reporting Research Research Institute Resistance Route Specificity Surface T cell therapy T memory cell T-Lymphocyte Technology Testing Therapeutic Effect Therapeutic Research Translating Treatment Efficacy Tumor Escape alternative treatment bench to bedside bi-specific T cell engager cancer cell chemotherapy chimeric antigen receptor chimeric antigen receptor T cells clinical efficacy clinical lot cytokine effective therapy experience first-in-human high risk improved in vivo innovation manufacture mouse model new therapeutic target novel novel therapeutics patient derived xenograft model patient population preclinical study prevent professor response safety assessment success targeted treatment timeline tumor

项目摘要

PROJECT SUMMARY B-cell acute lymphoblastic lymphoma (B-ALL) is a neoplasm of B-cell lymphoid precursors that typically affects children, but occurs in adults as well. While intensive multi-agent chemotherapy is highly effective in the pediatric population, outcomes remain poor in adults and high-risk patients. The recent introduction of blinatumomab and CD19-directed CAR T therapy has transformed the care of patients with relapsed and refractory (r/r) B-ALL. However, an increasing number of reports describe a high rate of post-treatment relapse due to acquired resistance to these immunotherapies, notably via down-regulation or loss of CD19 surface expression. CAR T cells that were recently developed against another target, CD22, showed similar shortcomings with relapses associated with diminished antigen expression. The search for alternative targets is therefore essential to overcoming antigen escape. To address this issue, we have developed CAR T cells against a new B-ALL target, the B-cell activating factor receptor (BAFF-R). BAFF-R is a marker of B cells that is also functionally expressed in B-ALL, including in patients with CD19-negative relapse. Although one of BAFF-R’s ligands (BAFF) has been successfully targeted for the treatment of autoimmune diseases, we are the first to have developed BAFF-R CAR T cells that are effective against B-cell malignancies in vivo, including in CD19-negative mouse models. Because BAFF-R is a critical regulator of B-cell function and survival, we can expect that the tumor’s ability to escape therapy by down-regulation of BAFF-R will be limited. While we anticipate clinical efficacy of BAFF-R CAR T cell therapy, dual targeting of CD19 and BAFF-R can prevent the emergence of resistance and improve clinical outcomes. Therefore, we are also developing bispecific CD19- BAFF-R CAR T cells that we aim to rapidly translate from the bench to the bedside. In Specific Aim 1, we will evaluate BAFF-R CAR T cell therapy in a first-in-human clinical trial in patients with r/r B-ALL who are ineligible for or have failed prior CD19-directed therapy. The trial, currently open at City of Hope, will use our TN/MEM- derived manufacturing platform, which yields a naïve/memory T-cell enriched T cell product and has shown remarkable efficacy and tolerability in B-ALL. We will conduct extensive correlative studies using cutting-edge technologies, such as assessing the kinetics of the CAR T cells and that of diverse cytokines, therapeutic effect, and potential mechanisms of relapse and antigen escape. In Specific Aim 2, we will establish the therapeutic efficacy of bispecific CD19-BAFF-R CAR T cells against mixed (CD19-negative + BAFF-R- negative) B-ALL tumor models that mimic the heterogenous tumor phenotype leading to resistance. We will also perform extensive testing of cGMP-grade bispecific CD19-BAFF-R CAR T cells that is required prior to submission of an IND application to the FDA. Our proposal addresses the urgent need for new therapeutic options in patients with r/r B-ALL and could also benefit patients with other B-cell malignancies.

项目摘要 B细胞急性淋巴细胞淋巴瘤（B-ALL）是B细胞淋巴前体的肿瘤，通常会影响儿童，但也发生在成年人中。虽然密集的多药化疗在成人和高风险患者的小儿种群，结果仍然很差。最近引入布里纳瘤和CD19导向的CAR T疗法已改变了继电器的患者的护理耐火（R/R）B-all。但是，越来越多的报告描述了高度处理后继电器的率由于获得了对这些免疫疗法的耐药性，特别是通过下调或CD19表面损失表达。最近针对另一个目标CD22开发的CAR T细胞显示了相似的与抗原表达降低有关的关系的缺点。寻找替代目标因此，对于克服抗原逃生至关重要。为了解决这个问题，我们已经开发了汽车T细胞针对新的B-all靶标，B细胞激活因子受体（BAFF-R）。 BAFF-R是B细胞的标记也在B-All功能上表达，包括CD19阴性救济的患者。虽然之一 Baff-R的配体（BAFF）已成功地用于治疗自身免疫性疾病，我们是第一个开发了对体内B细胞恶性肿瘤有效的BAFF-R CAR T细胞，包括在CD19阴性小鼠模型中。因为BAFF-R是B细胞功能和生存的关键调节剂，我们可以预计肿瘤通过下调BAFF-R逃脱治疗的能力将受到限制。当我们预期BAFF-R CAR T细胞疗法的临床效率，CD19和BAFF-R的双重靶向可以防止抵抗的出现并改善临床结果。因此，我们也正在开发双特异性CD19- 我们旨在从长凳上迅速转换为床边的Baff-R Car T细胞。在特定目标1中，我们将在不合格的R/R B-All患者中，评估Baff-R CAR T细胞疗法的首次人类临床试验对于先前的CD19定向治疗或未能通过。目前在希望之城开放的试验将使用我们的TN/MEM- 得出的制造平台，该平台产生幼稚/存储器T细胞富含T细胞产品 B-all的显着效率和耐受性。我们将使用前沿进行广泛的相关研究技术，例如评估CAR T细胞的动力学和潜水细胞因子的动力学，治疗继电器和抗原逃生的效果和潜在机制。在特定目标2中，我们将确定双特异性CD19-BAFF-R CAR T细胞的治疗效率（CD19阴性 + BAFF-R-）负）B-所有模仿异质肿瘤表型的肿瘤模型导致抗性。我们将还对CGMP级双特异性CD19-BAFF-R CAR T细胞进行大量测试向FDA提交IND申请。我们的建议解决了对新疗法的迫切需求 R/R B-all患者的选择，也可能使其他B细胞Malignancys患者受益。