Autologous CD19 Targeted 19-28z+ Tcells for the Treatment of Relapsed Diffuse Large B cell Lymphoma in Transplant Ineligible Elderly Patients

尽管目前有可用的化疗方案，但复发的弥漫性大B细胞淋巴瘤患者 (DLBCL)不符合自体干细胞移植(ASCT)条件的患者预后非常差，是一种 未得到满足的需求领域。出于这个原因，需要为这一患者群体提供新的方法。一本小说 目前在临床环境中正在研究的方法是采用遗传的T细胞转移 修饰以表达人工T细胞受体，称为嵌合抗原受体(CARS)，旨在识别 靶抗原表达于肿瘤细胞表面。为此，患者自己的T细胞可以被分离出来并 通过逆转录病毒或慢病毒基因转移修饰以表达CAR，从而将T细胞特异性重定向至 肿瘤相关抗原。大多数B细胞恶性肿瘤，包括大多数B细胞非霍奇金淋巴瘤 非霍奇金淋巴瘤(NHL)、慢性淋巴细胞白血病(CLL)和B细胞急性淋巴细胞白血病(B-ALL)表达B 细胞特异性抗原CD19。值得注意的是，大多数DLBCL类似地表达CD19抗原。到目前为止，我们和 其他几个小组最近报告了低级别和 针对CD19抗原的CAR T细胞治疗侵袭性B细胞癌。到目前为止，这些临床 研究报告了低级别B细胞CLL患者的抗肿瘤反应，而在 复发/难治性B-ALL患者。最近，一小部分患者的临床结果 CD19靶向CAR T细胞治疗复发的DLBCL显示出有希望但不理想 应答，7名患者中有4名完全缓解(CRS)，但4名患者中只有3名有效 相对耐用(9-22个月)，随访时间相对较短。一个额外的和相关的基于免疫的 癌症治疗的方法，最近才在 DLBCL自体骨髓干细胞移植后免疫关卡阻断 靶向T细胞PD-1受体的拮抗性单抗，当与PD-L1或 PD-L2配体诱导T细胞无能。因此，用PD-1特异性阻断这一T细胞检查点通路 单抗可能反过来增强肿瘤靶向T细胞的抗肿瘤功能，并可能进一步调节 否则免疫抑制的肿瘤微环境更适合免疫靶向肿瘤 通过CAR T细胞以及招募的内源性抗肿瘤免疫效应器来根除。初级阶段 该项目的目标是优化CD19靶向CAR T细胞治疗DLBCL患者。为此目的，在Aim 1我们将首先应用我们的CD19靶向19-28Z CAR T细胞方法来治疗预后非常差的老年人 复发/难治性ASCT不符合条件的DLBCL患者，这是一种代表未得到满足的医疗需求的情况 抢救化疗后作为单一药物治疗的I/II期临床试验。在目标2中，我们使用了一个 临床相关免疫活性DLBCL小鼠模型的建立及其与19-28Z联用的研究 使用PD-1检查点抑制进行CAR T细胞治疗，其中后者基于免疫的方法可能保护 来自PD-L1和PD-L2的CD19靶向CAR T细胞介导无能或凋亡，并有利地调节 肿瘤微环境。最后，在本提案的目标3中，我们将把这些研究转化回临床 设置计划中的第二阶段I/II临床试验，目标是相同的患者群体，旨在优化 19-28Z CAR T细胞治疗联合PD-1免疫关卡阻断的抗肿瘤作用

Despite currently available chemotherapy regimens, patients with relapsed diffuse large B cell lymphoma (DLBCL) ineligible for autologous stem cell transplant (ASCT) have a very poor prognosis and represent an area of unmet need. For this reason, novel approaches are needed for this patient population. One novel approach currently being investigated in the clinical setting is the adoptive transfer of T cells genetically modified to express artificial T cell receptors termed chimeric antigen receptors (CARs) designed to recognize target antigens expressed on the tumor cell surface. To this end, a patient’s own T cells may be isolated and through retroviral or lentiviral gene transfer modified to express the CAR thereby redirecting T cell specificity to the tumor associated antigen. Most B cell malignancies, including most B cell non-Hodgkins lymphomas (NHL), chronic lymphocytic leukemias (CLL) and B cell acute lymphoblastic leukemias (B-ALL) express the B cell specific antigen CD19. Significantly, most DLBCLs similarly express the CD19 antigen. To date we and several other groups have recently reported initial clinical outcomes of patients with both low grade as well as aggressive B cell cancers treated with CAR T cells targeted to the CD19 antigen. To date, these clinical studies have reported anti-tumor responses in patients with low grade B cell CLL and far more markedly in patients with relapsed/refractory B-ALL. More recently, clinical outcomes of a small cohort of patients with relapsed DLBCL treated with CD19 targeted CAR T cells have demonstrated promising but suboptimal responses, with 4 of 7 patients demonstrating complete remissions (CRs) but only 3 of 4 responses being relatively durable (9-22 months) with relatively short follow-up. An additional and relevant immune-based approach to cancer therapy, having only recently demonstrated moderate clinical benefit in the setting of DLBCL after autologous bone marrow stem cell transplantation, is immune-checkpoint blockade through infusion of antagonistic MAb’s targeted to the T cell PD-1 receptor, which when engaged to either the PD-L1 or PD-L2 ligand induces T cell anergy. As a result, blockade of this T cell checkpoint pathway with PD-1 specific MAbs may in turn enhance the anti-tumor function of tumor targeted T cells and may further modulate an otherwise immune suppressive tumor microenvironment to one more suitable for immune targeted tumor eradication by both CAR T cells as well as recruited endogenous anti-tumor immune effectors. The primary goal of this project is to optimize CD19 targeted CAR T cell therapy in patients with DLBCL. To this end in Aim 1 we will initially apply our CD19 targeted 19-28z CAR T cell approach to very poor prognosis elderly relapsed/refractory ASCT ineligible DLBCL patients, a condition representing an unmet medical need, in a phase I/II clinical trial as a single agent therapy following salvage chemotherapy. In Aim 2 we utilize a clinically relevant immune competent murine model of DLBCL to investigate the rationale of combining 19-28z CAR T cell therapy with PD-1 checkpoint inhibition wherein the latter immune-based approach may protect the CD19 targeted CAR T cells from PD-L1 and PD-L2 mediated anergy or apoptosis and favourably modulate the tumor microenvironment. Finally, in Aim 3 of this proposal we will translate these studies back into the clinical setting in a planned second phase I/II clinical trial targeting the same patient population designed to optimize the anti-tumor efficacy with 19-28z CAR T cell therapy combined with PD-1 immune checkpoint blockade.