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：
10420774
负责人：
IBRAHIM ALDOSS
金额：
$ 67.76万
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/10420774
关键词：
Acute Address Adult Affect Aftercare Alternative Therapies Antibodies 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 Disease remission Dose Down-Regulation Enrollment Epitopes FDA approved Failure Generations Genetic Engineering Hematologic Neoplasms Human Engineering Immune Immunotherapy In Vitro Interleukin 4 Receptor Kinetics Laboratory Research Lead 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 Recurrence Refractory Relapse Reporting Research Research Institute Resistance Route Safety Specificity Surface T cell therapy T memory cell T-Lymphocyte Technology Testing Therapeutic Effect Therapeutic Human Experimentation TimeLine Translating Treatment Efficacy Tumor Escape alternative treatment base 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 mouse model new therapeutic target novel novel therapeutics patient derived xenograft model patient population preclinical study prevent professor relapse patients response success targeted treatment 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.

项目概要 B 细胞急性淋巴细胞淋巴瘤 (B-ALL) 是一种 B 细胞淋巴前体肿瘤，通常影响儿童，但也发生在成人中，而强化多药化疗对于该患者非常有效。儿童人群中，成人和高危患者的结果仍然较差。 blinatumomab 和 CD19 导向的 CAR T 疗法改变了复发和难治性癌症患者的护理然而，越来越多的报告描述了治疗后复发率很高。由于对这些免疫疗法的获得性耐药，特别是通过 CD19 表面的下调或丧失最近开发的针对另一个靶标 CD22 的 CAR T 细胞也表现出类似的表达。与抗原表达减少相关的复发缺点。因此，对于克服抗原逃逸至关重要。为了解决这个问题，我们开发了 CAR T 细胞。针对新的 B-ALL 靶点，B 细胞激活因子受体 (BAFF-R) 是 B 细胞的标记物。在 B-ALL 中也有功能性表达，包括 CD19 阴性复发的患者。 BAFF-R的配体（BAFF）已成功靶向治疗自身免疫性疾病，我们正在第一个开发出 BAFF-R CAR T 细胞，可有效对抗体内 B 细胞恶性肿瘤，包括在 CD19 阴性小鼠模型中，由于 BAFF-R 是 B 细胞功能和存活的关键调节因子，因此我们可以预计肿瘤通过下调 BAFF-R 逃避治疗的能力将受到限制。预测 BAFF-R CAR T 细胞疗法的临床疗效，CD19 和 BAFF-R 的双重靶向可以预防因此，我们还在开发双特异性 CD19-。我们的目标是将 BAFF-R CAR T 细胞快速从实验室转移到临床。在首次人体临床试验中对不符合条件的 r/r B-ALL 患者评估 BAFF-R CAR T 细胞疗法先前针对 CD19 的治疗或已失败该试验目前在 City of Hope 开放，将使用我们的 TN/MEM- 衍生的制造平台，产生了一种幼稚/记忆 T 细胞富集的 T 细胞产品，并已证明我们将利用尖端技术进行广泛的相关研究。技术，例如评估 CAR T 细胞和多种细胞因子的动力学、治疗在具体目标 2 中，我们将确定复发和抗原逃逸的潜在机制。双特异性CD19-BAFF-R CAR T细胞对混合（CD19阴性+ BAFF-R- 阴性）B-ALL 肿瘤模型模拟导致耐药的异质肿瘤表型。还对 cGMP 级双特异性 CD19-BAFF-R CAR T 细胞进行广泛的测试，这是在向 FDA 提交 IND 申请解决了对新疗法的迫切需求。复发/难治性 B-ALL 患者的选择，也可能使其他 B 细胞恶性肿瘤患者受益。