Project 1: Overcoming resistance of B cell leukemia to CD19 CAR T Cells.

总结(项目1) 抗CD19嵌合抗原受体重定向T细胞(CART-19)对一些人来说是非常成功的 患有B细胞恶性肿瘤的患者。我们和其他公司在以下方面显示完全响应(CR)率超过90% 复发/难治(r/r)ALL患者。其中许多缓解是持续的，但主要限制是 20-50%的患者复发，其中三分之二的复发与CD19阴性的ALL有关。在有r/r的患者中 用抗CD19 CAR T细胞治疗CLL，完全应答率较低，为20%-25%，但在治疗后复发 缓解是非常不寻常的。此外，还有许多B细胞恶性肿瘤患者无法 受益于CAR T细胞，因为无法收集或制造T细胞，特别是从密集的 治疗T细胞计数低的患者和婴儿。此外，一些患者病情会迅速恶化，之前 制造是完整的，不能容忍或存活必要的治疗延迟。 该项目将使用全面的战略来针对CAR T细胞治疗的主要限制，增加 通过同时观察T细胞的内在和外在，这种已经转变的方法的可行性 耐药机制以及导致复发的所有细胞内在机制。我们会带上 与拥有基因专业知识的核心实验室建立成功合作的优势 编辑学，以及最新的相关科学，探索了一些创新的目的。我们有 设计研究以了解CD19阴性和CD19背后的生物学和机制 总而言之，复发是积极的。在CLL中，响应率是比复发更重要的障碍，我们将 探索检查点分子、肿瘤微环境和白血病细胞本身在其中所起的作用 诱导对CTL019的抗性。为此，我们将利用我们独特的样本库，这些样本库来自 超过200名患者在儿童医院和宾夕法尼亚大学接受CTL019治疗。最后，我们设计了高 Impact临床试验1)测试方法以限制CD19阴性复发(通过靶向CD19和CD22 同时)和2)通过检测经基因编辑、CAR修饰的 同种异体T细胞(“PACE”汽车)。佩斯汽车是预先制造的，“通用捐赠者”汽车+细胞是 用CRISPR技术进行基因编辑，消除T细胞受体和人类白细胞抗原I类分子。这些细胞可以 可跨越人类白细胞抗原屏障使用，不应引起移植物抗宿主病或被迅速排斥。因此，他们可以解决 自体汽车疗法中未得到满足的医疗需求：i)有高度的临床紧迫性(细胞 立即可用)；ii)未能采集足够的T细胞或制造自体汽车 以及iii)自体CTL019未能诱导B细胞再生障碍性贫血和/或临床反应。这 研究将具有非常重要的意义，因为它将导致对抗病机制的详细了解。 CTL019，提供可快速翻译用于临床测试的信息，并执行高度创新 临床试验试图改善目前没有有效治疗选择的患者的结果。

SUMMARY (PROJECT 1) Anti-CD19 chimeric antigen receptor redirected T cells (CART-19) have been dramatically successful for some patients with B-cell malignancies. We and others have shown complete response (CR) rates of over 90% in patients with relapsed/refractory (r/r) ALL. Many of these remissions are sustained, but the major limitation is relapse in 20-50% of patients and two-thirds of these relapses involve CD19-negative ALL. In patients with r/r CLL treated with anti-CD19 CAR T cells, complete response rates are lower at 20-25%, but relapse after remission is very unusual. In addition, there are also many patients with B cell malignancies who cannot benefit from CAR T cells because of the inability to collect or manufacture T cells, especially from intensively treated patients with low T cell counts and from infants. In addition, some patients will rapidly progress before manufacturing is complete and cannot tolerate or survive the necessary treatment delay. This project will use a comprehensive strategy to target the major limitations in CAR T cell therapy, increasing the feasibility of this already transformational approach by looking both at T cell-intrinsic and extrinsic mechanisms of resistance as well as ALL cell-intrinsic mechanisms that lead to relapse. We will take advantage of already established successful collaborations with core laboratories with expertise in gene editing, as well as state of the art correlative science to explore a number of innovative aims. We have designed studies to understand the biology and mechanisms underlying both CD19 negative and CD19 positive relapse in ALL. In CLL, where response rates are a more significant barrier than relapse, we will explore the role that checkpoint molecules, the tumor microenvironment, and the leukemia cell itself plays in inducing resistance to CTL019. To do this, we will capitalize on our unique bank of specimens derived from over 200 patients treated at Children's Hospital and U Penn with CTL019. Finally, we have designed high impact clinical trials 1) testing methods to limit CD19 negative relapse in ALL (by targeting CD19 and CD22 concurrently) and 2) enhancing responses in B cell malignancies by testing gene-edited, CAR modified allogeneic T cells (“PACE” CARs). PACE CARs are pre-manufactured, “universal donor” CAR+ cells that are gene-edited with CRISPR technology to eliminate T cell receptors and HLA class I molecules. These cells could be used across HLA barriers and should not cause GVHD or be rapidly rejected. Therefore, they can solve unmet medical needs in autologous CAR therapy where i) there is a high degree of clinical urgency (cells are immediately available); ii) there has been a failure to collect adequate T cells or manufacture autologous CAR cells; and iii) where autologous CTL019 has failed to induce B cell aplasia and/or clinical response. This research will be highly significant because it will lead to detailed understanding of mechanisms of resistance to CTL019, provide information that can be rapidly translated for clinical testing, and perform highly innovative clinical trials attempting to enhance outcomes for patients who currently have no effective treatment options.