BAFF-R CAR T cell therapy for ALL

项目摘要 B细胞急性淋巴母细胞性淋巴瘤（B-ALL）是一种B细胞淋巴样前体肿瘤， 儿童，但也发生在成年人身上。虽然密集的多药剂化疗在癌症中是非常有效的， 儿童人群中，成人和高危患者的结局仍然较差。最近采用 Blinatumomab和CD 19导向的CAR T治疗已经改变了复发性和复发性乳腺癌患者的护理， 难治性（r/r）B-ALL。然而，越来越多的报告描述了治疗后复发率高 由于对这些免疫疗法的获得性抗性，特别是通过下调或丧失CD 19表面 表情最近针对另一个靶点CD 22开发的CAR T细胞显示出类似的结果。 与减少的抗原表达相关的复发的缺点。寻找替代目标 因此对于克服抗原逃逸是必不可少的。为了解决这个问题，我们开发了CAR T细胞， 针对一种新的B-ALL靶点，B细胞活化因子受体（BAFF-R）。BAFF-R是B细胞的标志物， 在B-ALL中也有功能性表达，包括CD 19阴性复发患者。虽然其中一 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CD 19阴性小鼠模型中。因为BAFF-R是B细胞功能和存活的关键调节因子，我们可以 预期肿瘤通过下调BAFF-R逃避治疗的能力将受到限制。虽然我们 预期BAFF-R CAR T细胞疗法的临床疗效，CD 19和BAFF-R的双重靶向可以预防 耐药性的出现和改善临床结果。因此，我们也在开发双特异性CD 19- 我们的目标是将BAFF-R CAR T细胞从实验室快速转化到床边。具体目标1： 在不符合条件的r/r B-ALL患者的首次人体临床试验中评估BAFF-R CAR T细胞疗法 既往接受过CD 19导向治疗或治疗失败。目前在City of Hope开放的试验将使用我们的TN/MEM- 衍生的制造平台，其产生幼稚/记忆T细胞富集的T细胞产物，并已显示 在B-ALL中具有显著的疗效和耐受性。我们将利用尖端技术进行广泛的相关研究， 技术，如评估CAR T细胞的动力学和各种细胞因子的动力学，治疗性 影响，复发和抗原逃逸的潜在机制。在具体目标2中，我们将建立 双特异性CD 19-BAFF-R CAR T细胞对混合（CD 19阴性+ BAFF-R-CAR T细胞）的治疗功效 阴性）B-ALL肿瘤模型，其模拟导致耐药性的异质性肿瘤表型。我们将 还对cGMP级双特异性CD 19-BAFF-R CAR T细胞进行了广泛的测试， 向FDA提交IND申请。我们的建议解决了对新的治疗方法的迫切需要， 在r/r B-ALL患者中的选择，也可能使其他B细胞恶性肿瘤患者受益。

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.