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

尽管目前可用的化疗方案，复发性弥漫性大B细胞淋巴瘤患者 不适合自体干细胞移植（ASCT）的DLBCL患者预后非常差， 未满足的需求。因此，需要针对该患者人群的新方法。一个新颖 目前在临床环境中研究的方法是将T细胞遗传性地过继转移 被修饰以表达称为嵌合抗原受体（汽车）的人工T细胞受体， 肿瘤细胞表面表达的靶抗原。为此，可以分离患者自身的T细胞， 通过逆转录病毒或慢病毒基因转移修饰以表达CAR，从而重定向T细胞特异性， 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 (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CD 19。值得注意的是，大多数DLBCL类似地表达CD 19抗原。到目前为止，我们和 其他几个研究小组最近报道了低级别以及 用靶向CD 19抗原的CAR T细胞治疗的侵袭性B细胞癌。迄今为止，这些临床 研究已经报道了低级别B细胞CLL患者的抗肿瘤应答， 复发/难治性B-ALL患者。最近，一个小队列的患者的临床结果， 用靶向CD 19的CAR T细胞治疗的复发性DLBCL已经证明是有希望的，但不是最佳的 反应，7例患者中有4例显示完全缓解（CR），但4例反应中只有3例 相对持久（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，最近才证明在以下情况下有中度临床获益： 自体骨髓干细胞移植后的DLBCL，是否通过免疫检查点阻断 输注靶向T细胞PD-1受体的拮抗性MAb，当其与PD-L1或PD-L2结合时， PD-L2配体诱导T细胞无能。因此，用PD-1特异性阻断这种T细胞检查点途径， MAb可以反过来增强肿瘤靶向T细胞的抗肿瘤功能，并可以进一步调节肿瘤细胞的增殖。 否则免疫抑制性肿瘤微环境变得更加适合免疫靶向肿瘤 通过CAR T细胞以及募集的内源性抗肿瘤免疫效应物两者的根除。主 该项目的目标是优化DLBCL患者中的CD 19靶向CAR T细胞疗法。为此目的， 1我们将首先将我们的CD 19靶向19- 28 z CAR T细胞方法应用于预后非常差的老年人， 复发性/难治性ASCT不合格DLBCL患者，代表未满足的医疗需求的疾病， I/II期临床试验，作为补救化疗后的单药治疗。在目标2中，我们使用 临床相关的DLBCL免疫活性鼠模型，以研究联合19- 28 z 具有PD-1检查点抑制的CAR T细胞疗法，其中后一种基于免疫的方法可以保护CAR T细胞。 来自PD-L1和PD-L2的靶向CD 19的CAR T细胞介导无反应性或凋亡，并有利地调节免疫应答。 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为临床研究。 在计划的第二个I/II期临床试验中，针对相同的患者人群， 19- 28 z CAR T细胞疗法与PD-1免疫检查点阻断相结合的抗肿瘤功效。

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.