BAFF-R CAR T cell therapy for ALL

项目总结 B细胞急性淋巴母细胞淋巴瘤(B-ALL)是一种B细胞淋巴前体肿瘤，通常影响 儿童，但也发生在成年人身上。虽然强化多药化疗在初治患者中非常有效 在儿童人群中，成人和高危患者的预后仍然很差。最近推出的 Blinatumomab和CD19指导的CAR T疗法改变了复发和 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很高。 由于对这些免疫疗法的获得性抵抗，特别是通过下调或丢失CD19表面 表情。最近针对另一个靶点CD22开发的CAR T细胞也显示出类似的情况 与抗原表达减弱相关的复发缺陷。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 针对一个新的B-ALL靶点，B细胞激活因子受体(BAFF-R)。BAFF-R是B细胞的标志物 在B-ALL中也有功能表达，包括在CD19阴性复发患者中。尽管其中一位 BAFF-R的配体(BAFF)已成功用于治疗自身免疫性疾病，我们 第一个在体内开发出对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细胞功能和存活的关键调节因子，我们可以 预计肿瘤通过下调BAFF-R来逃避治疗的能力将是有限的。当我们 预期BAFF-R CAR T细胞治疗的临床疗效，CD19和BAFF-R双靶向可预防 出现耐药，改善临床预后。因此，我们还在开发双特异性CD19- 我们的目标是将BAFF-R CAR的T细胞从长椅上迅速移植到床边。在具体目标1中，我们将 对不符合条件的r/r B-ALL患者进行首例人类临床试验，评估BAFF-R CAR T细胞治疗 接受或失败了之前的CD19指导治疗。目前在希望之城开始的试验将使用我们的TN/MEM- 衍生制造平台，生产幼稚/记忆性T细胞富集型T细胞产品，并已显示 对B-ALL有显著疗效和耐受性。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细胞和各种细胞因子的动力学，具有治疗性 复发和抗原逃逸的影响和潜在机制。在具体目标2中，我们将建立 CD19-BAFF-R CAR双特异性T细胞对混合(CD19-+BAFF-R-)T细胞的治疗作用 阴性)B-ALL肿瘤模型模仿导致耐药的异源肿瘤表型。我们会 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。我们的建议解决了对新疗法的迫切需求 对r/r B-ALL患者的选择，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.