Improved Chimeric Antigen Receptor Therapies B-cell Malignancies

改进的嵌合抗原受体疗法 B 细胞恶性肿瘤

• 批准号: 10014668
• 负责人: James Kochenderfer
• 金额: $ 66.72万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10014668
• 关键词: Adoptive Transfer; Affect; American Society of Hematology; Antigens; B cell therapy; B lymphoid malignancy; B-Cell Lymphomas; B-Lymphocytes; Binding; Biological; CD19 gene; CD20 Antigens; CD28 gene; CD3 Antigens; CD8 Antigens; CD8B1 gene; Cell Death; Clinical; Clinical Oncology; Clinical Trials; Disease remission; Effectiveness; Enrollment; Evaluable Disease; FDA approved; Human; Immunoglobulin Variable Region; Infusion procedures; Interleukin-15; Investigational New Drug Application; Journals; Knowledge; Lead; Lymphoma; MS4A1 gene; Molecular; Monoclonal Antibodies; Mus; Neurologic; Oral; Paper; Patients; Principal Investigator; Production; Proliferating; Publishing; Reporting; Research Personnel; Serum; T-Cell Activation; T-Lymphocyte; Testing; Toxic effect; Transmembrane Domain; Work; anti-CD20; cancer cell; cellular transduction; chimeric antigen receptor; chimeric antigen receptor T cells; curative treatments; cytokine; design; extracellular; falls; genetically modified cells; improved; in vitro Assay; in vitro testing; large cell Diffuse non-Hodgkin' s lymphoma; leukemia/lymphoma; meetings; novel; novel therapeutics; pre-clinical; receptor function; response; tumor; vector

In the past year, this project has consisted of testing multiple factors that could affect the function of chimeric antigen receptors (CARs). Chimeric antigen receptors consist of several components, the antigen-recognition moiety that is usually derived from a monoclonal antibody, a extracellular region that connects the antigen-recognition moiety to the transmembrane portion, costimulatory domains such as 4-1BB and CD28, and T cell activation domains such as CD3-zeta. We were among the first investigators to test anti-CD19 CAR T cells. In the past year, we published important results in the Journal of Clinical Oncology reporting a 73% overall response rate when patients with advanced lymphoma were treated with anti-CD19 CAR T cells. This same work also reported the important association between serum interleukin-15 levels and anti-lymphoma responses. We also reported the longest continuous complete remissions of diffuse large B-cell lymphoma that was treated with anti-CD19 CAR T cells. Four patients with complete remissions of 38 to 56 months were reported in a paper that is in press at Molecular Therapy. We have constructed multiple new CARs over the past 2 years to test various components of CARs. T cells are transduced with the various CARs by using a gammaretroviral vector, and in vitro assays are carried out. The aim is to find CARs that impart T cells with the ability to kill cancer cells and proliferate without producing large amounts of potentially toxic inflamatory cytokines. We have found that changing the hinge and transmembrane regions, costimulatory domains, or T cell activation domains all cause profound differences in CAR function. Following extensive in vitro testing, we found that CARs with hinge and transmembrane regions from CD8 led to lower levels of cytokine production and activation-induced cell death than CARs with hinge and transmembrane regions from CD28. CARs with either CD8 or CD28 hinge and transmembrane regions could both eliminate tumors from mice. This work has resulted a paper in press at Molecular Therapy. This work has also lead to a new fully-human anti-CD19 CAR that is currently being tested in a clinical trial. We have enrolled 16 patients on a clinical trial of the CAR resulting from this work. The CAR is called Hu19-CD828Z. It has hinge and transmembrane regions from the CD8 molecule. Of 16 treated patients, 15 patients are evaluable for anti-lymphoma response so far. The overall response rate is 73% and the complete remission rate is 47%. One notable preliminary finding is a decreased rate of severe neurologic toxicity compared to previous anti-CD19 CAR clinical trials. This work resulted in an oral presentation at the American Society of Hematology meeting in December 2016. We have completed a formal comparison of the new Hu19-CD828Z CAR to our previously-used FMC63-28Z CAR. We found a 5% rate of Grade 3 or 4 clinical neurologic toxicity with teh new Hu19-CD828Z CAR versus a 50% rate of Grade 3 or 4 clinical neurologic toxicity with the older FMC63-28Z CAR. We have found lower levels of cytokine production with T cells expressing Hu19-CD828Z versus T cells expressing FMC63-28Z. Another aspect of this project is developing CARs against B-cell antigens other than CD19. We have developed 3 functional CARs that target the B-cell antigen CD20. We plan to utilize this knowledge of anti-CD20 CARs to either conduct a clinica trial of an anti-CD20 CAR or to design a bispecific CAR including CD20 binding and a domain targeting another B-cell antigen. Targeting more than 1 antigen simultaneously is important because many cases of lymphoma do not express CD19. We have selected an optimal bicistronic CAR construct that targets both CD19 and CD20. The bicistronic construct encodes 2 CARs, one of the CARs is the previously -described Hu19-CD828Z CAR. The second CAR is an anti-CD20 CAR designated Hu20-CD8BBZ. The entire bicistronic construct is designated Hu19-CD828-Hu20BB, and the construct is encoded by a gammaretroviral vector. We have submitted an Investigational New Drug Application (IND) to the FDA in order to test T cells transduced with this bicistronic construct in humans. We plan to initiate a clinical trial treating lymphoma patients with these T cells in the fall of 2019.

在过去的一年中，该项目包括测试可能影响嵌合抗原受体（CARS）功能的多个因素。嵌合抗原受体由几个成分组成，几个成分是抗原识别部分，通常源自单克隆抗体，单克隆抗体是一个将抗原识别部分连接到跨膜部分的细胞外区域，即跨膜部分，costimultim of Cypimultorative域，例如4-1B和T细胞激活域，例如4-1BB和CD33-cd3-cd3-cd3-cd3-szeta。我们是最早测​​试抗CD19 CAR T细胞的研究者。在过去的一年中，我们在《临床肿瘤学杂志》中发表了重要的结果，报告了晚期淋巴瘤患者用抗CD19 CAR T细胞治疗的总体缓解率73％。同样的工作还报道了血清白介素15水平与抗淋巴瘤反应之间的重要关联。我们还报道了用抗CD19 CAR T细胞处理的最长连续完全消除大型B细胞淋巴瘤。在分子疗法的新闻报道中，有四名完全缓解38至56个月的患者。在过去的两年中，我们已经建造了多辆新车，以测试汽车的各种组件。通过使用γ逆转录病毒载体将T细胞用各种汽车转导，并进行体外测定。目的是找到能够杀死癌细胞和增殖的T细胞的汽车，而无需产生大量潜在的毒性炎性细胞因子。我们已经发现，改变铰链和跨膜区域，共刺激域或T细胞活化域都会在CAR功能上产生深远的差异。经过广泛的体外测试，我们发现与CD28的铰链和激活诱导的细胞死亡相比，CD8的铰链和跨膜区域的汽车导致细胞因子产生和激活诱导的细胞死亡水平较低。具有CD8或CD28铰链和跨膜区域的汽车都可以消除小鼠的肿瘤。这项工作导致了在分子治疗的新闻中发表论文。这项工作还导致了新的全人类抗CD19汽车，该汽车目前正在临床试验中进行测试。我们已经招募了16名患者接受这项工作的临床试验。该车称为HU19-CD828Z。它具有来自CD8分子的铰链和跨膜区域。在16名治疗患者中，到目前为止，可评估15例抗淋巴瘤反应的患者。总体响应率为73％，完整缓解率为47％。一个值得注意的初步发现是与以前的抗CD19 CAR临床试验相比，严重神经毒性的率降低。这项工作导致在2016年12月的美国血液学协会会议上进行了口头介绍。我们已经完成了新的HU19-CD828Z汽车与以前使用的FMC63-28Z汽车的正式比较。我们发现3级或4级临床神经系统毒性的速率为新的HU19-CD828Z汽车，而3级或4级的临床神经系统毒性率为50％，而较旧的FMC63-28Z汽车。我们发现用表达HU19-CD828Z的T细胞与表达FMC63-28Z的T细胞的T细胞的细胞因子产生较低。该项目的另一个方面是针对CD19以外的B细胞抗原开发汽车。我们已经开发了3种靶向B细胞抗原CD20的功能性汽车。我们计划利用这种抗CD20汽车的知识来进行抗CD20汽车的临床试验，或设计（包括CD20结合和针对其他B细胞抗原）的双特异性汽车。同时靶向1个以上的抗原很重要，因为许多淋巴瘤病例不表达CD19。我们选择了一个针对CD19和CD20的最佳双散发汽车构建体。 Bicistronic构造编码2辆汽车，其中一辆是先前描述的HU19 -CD828Z汽车。第二辆车是指定HU20-CD8BBZ的抗CD20汽车。整个Bicistronic构建体被指定为HU19-CD828-HU20BB，该构建体由Gammaretroviral载体载体编码。我们已向FDA提交了研究新药物应用（IND），以测试用这种双散发器在人类中转导的T细胞。我们计划在2019年秋天开始进行这些T细胞淋巴瘤患者的临床试验。