CMV/CD19 bi-Specific CAR T cells combined with CMV vaccine as post-transplantation immunotherapy for non-Hodgkin lymphoma

CMV/CD19双特异性CAR T细胞联合CMV疫苗作为非霍奇金淋巴瘤移植后免疫治疗

• 批准号: 10242159
• 负责人: Stephen J Forman
• 金额: $ 31.65万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-02 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242159
• 关键词: Ablation; Acute Lymphocytic Leukemia; Address; Adoptive Immunotherapy; Adoptive Transfer; Adult; Allogenic; Antigens; Attenuated; Autologous; B-Cell NonHodgkins Lymphoma; Biometry; CAR T cell therapy; CD19 gene; Cells; Cities; Clinical; Clinical Trials; Correlative Study; Cyclic GMP; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Data; Development; Diamond; Disease; Dose-Limiting; Effectiveness; Engineering; Engraftment; Epidermal Growth Factor Receptor; Feasibility Studies; Frequencies; Funding; Genes; Grant; Hematopoietic Stem Cell Transplantation; Immune; Immunity; Immunology; Immunotherapy; In Vitro; Infusion procedures; Injections; Laboratories; Leukapheresis; Lymphoma; Malignant Neoplasms; Mediating; Methods; Modification; Modified Vaccinia Virus Ankara; Non-Hodgkin' s Lymphoma; Patient-Focused Outcomes; Patients; Peripheral Blood Mononuclear Cell; Phase; Pilot Projects; Progression-Free Survivals; Property; Proteins; Recombinant modified vaccinia virus Ankara; Recurrent disease; Refractory; Relapse; Research Personnel; Risk; Safety; Series; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Therapeutic; Time; TimeLine; Toxic effect; Transplant Recipients; Treatment Failure; Vaccination; Vaccines; Viral Antigens; anti-tumor immune response; base; chemoradiation; chemotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; conditioning; density; design; engineered T cells; experience; feasibility trial; graft vs host disease; healthy volunteer; hematopoietic cell transplantation; high risk; immunogenic; improved; in vivo; innovation; interest; neoplastic cell; non-Hodgkin' s lymphoma patients; novel; novel strategies; phase I trial; post-transplant; preclinical study; premature; prevent; relapse risk; response; senescence; seropositive; vaccine trial

SUMMARY Disease relapse is a leading cause of treatment failure after autologous (auto) and allogeneic (allo) hematopoietic stem cell transplantation (HCT) for patients with non-Hodgkin lymphoma (NHL). Accordingly, there is intense interest in using adoptive cellular immunotherapy to eradicate the limited number of tumor cells surviving after conditioning chemo-radiotherapy. For patients unable to undergo HCT or having relapsed post- HCT, this strategy may offer an option with curative intent. Chimeric Antigen Receptor (CAR)-engineered T cells have emerged as a promising treatment for relapsed/refractory CD19+ malignancies, but the full potential of this therapy is hampered by attenuated engraftment and lack of long-term persistence of CAR redirected T cells in patients. We propose a novel approach to improve efficacy and durability of CAR T cells based on properties of cytomegalovirus (CMV)-specific T cells and their expansion using a CMV vaccine, Triplex, recently developed and clinically evaluated at City of Hope. Triplex is a multi-antigen recombinant modified vaccinia Ankara (MVA) virus with genes encoding 3 CMV proteins, pp65, IE1, and IE2. CMV-MVA Triplex has proven safe and powerfully immunogenic in both CMV-seronegative and -seropositive healthy volunteers in a Phase I trial, and is now undergoing testing in alloHCT recipients. Our approach entails selecting CMVpp65- specific T cells for ex vivo modification with a CD19-targeting CAR, infusing the bi-specific CMV-CD19 CAR T cells into patients, and then inducing in vivo expansion by stimulating the native CMV-specific T cell receptor (TCR) using Triplex injections. Our strategy will shorten CAR T cell manufacturing time, with the dual advantage of preventing premature senescence of the infused cell product, and of making the product more rapidly available. Also, the truncated epidermal growth factor receptor (EGFRt) in our CAR design will act as both a tracking marker and an in vivo safety switch for ablating the CAR T cells. The proposed strategy is designed to enhance proliferation, lengthen persistence and augment the anti-lymphoma activity of adoptively transferred CMV-CD19 CAR T cells by re-stimulating these cells through the native CMVpp65-specific TCR. This should result in improved progression-free survival for NHL patients. The innovative aspect of this proposal is the substitution of in vitro expansion of the infused cell product with a novel in vivo expansion strategy. In Specific Aim 1 (SA1) we will validate this bi-specific CMV-CD19 CAR T cell manufacturing platform under cGMP conditions to produce clinical grade and scale cell products. In Specific Aims 2 and 3, we will test the CMV-CD19 CAR T cells therapy followed by Triplex vaccine in pilot studies for patients with relapsed- refractory B-cell NHL following autoHCT or lymphodepletion (SA2), or alloHCT (SA3). The significance of this approach is that we will have in vivo control of adoptively infused CMV-CD19 CAR T cell expansion and ablation. This project serves as a proof of principle for a method of enhancing CAR effectiveness and controlling T cell expansion that can potentially be applied to multiple diseases in multiple therapeutic settings.

概括 疾病复发是自体（自动）和同种异体（Allo）后治疗失败的主要原因 非霍奇金淋巴瘤（NHL）患者的造血干细胞移植（HCT）。因此， 人们对使用产卵性细胞免疫疗法消除有限数量的肿瘤细胞有很大的兴趣 调节化学疗法后存活。对于无法接受HCT或复发的患者 HCT，此策略可能会提供具有治愈性的选择。嵌合抗原受体（CAR）工程T 细胞已成为复发/难治性CD19+恶性肿瘤的有前途的治疗方法 这种疗法受到减毒的植入和缺乏长期持续性的抑制作用。 患者的细胞。我们提出了一种新的方法，以提高基于CAR T细胞的功效和耐用性 巨细胞病毒（CMV）特异性T细胞的特性及其使用CMV疫苗的扩展，Triplex， 最近在希望之城进行了开发和临床评估。 Triplex是一种多抗原重组修饰 vocinia ankara（MVA）病毒带有编码3 CMV蛋白的基因，PP65，IE1和IE2。 CMV-MVA Triplex具有 在CMV辅音和 - 垂直阳性的健康志愿者中，被证明是安全且有力的免疫原性 I期试验，现在正在AllOHCT接受者中进行测试。我们的方法需要选择CMVPP65- 特定的T细胞用CD19靶向的汽车进行体内修饰，并注入BI特异性CMV-CD19 CAR T 细胞进入患者，然后通过刺激天然CMV特异性T细胞受体诱导体内膨胀 （TCR）使用Triplex注射。我们的策略将缩短汽车T细胞制造时间，并使用双重 防止注入细胞产品过早衰老的优势，并使产品更大 迅速可用。同样，我们的汽车设计中的截短的表皮生长因子受体（EGFRT）将充当 跟踪标记和体内安全开关，用于消融CAR T细胞。拟议的策略是 旨在增强增殖，延长持久性并增强采用的抗淋巴瘤活性 通过天然CMVPP65特异性TCR重新刺激这些细胞，转移了CMV-CD19 CAR T细胞。 这应该导致NHL患者无进展的生存率提高。创新的方面 提案是用新型体内扩张的体外扩展的体外扩展 战略。在特定的目标1（SA1）中，我们将验证此双重CMV-CD19 CAR T细胞制造平台 在CGMP条件下，生产临床等级和尺度细胞产物。在特定目标2和3中，我们将测试 CMV-CD19 CAR T细胞治疗，然后是三元疫苗在试点研究中，用于复发的患者 自动驾驶或淋巴结膜（SA2）或alloHCT（SA3）后的耐火B-cell NHL。这一点的意义 方法是，我们将在体内控制采用的CMV-CD19 CAR T细胞扩展和 消融。该项目是提高汽车有效性和的原理证明 控制T细胞扩展，可能会在多种治疗环境中应用于多种疾病。