Clinical Development of Immunotherapies for Rare Hematologic Maligancies

罕见血液恶性肿瘤免疫疗法的临床开发

• 批准号: 10262549
• 负责人: Nirali Shah
• 金额: $ 20.55万
• 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/10262549
• 关键词: Acute Myelocytic Leukemia; Adolescent; Adolescent and Young Adult; Adult; Adverse event; Allogenic; Antibody Therapy; Antigens; B-Cell Lymphomas; Biological Models; Blood; Bone Marrow; CAR T cell therapy; CD28 gene; Cell Line; Cells; Child; Childhood; Childhood Acute Myeloid Leukemia; Clinical; Data; Development; Disease remission; Disease-Free Survival; Engraftment; Enrollment; FDA approved; Flow Cytometry; Future; Gemtuzumab Ozogamicin; Generations; Genotype; Hematology; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Hepatotoxicity; IL3RA gene; Immunotherapeutic agent; Immunotherapy; In Vitro; Incidence; Inferior; Infrastructure; Infusion procedures; Interferons; Interleukin-2; Luciferases; Manuscripts; Marrow; Maximum Tolerated Dose; Measures; Membrane Glycoproteins; Modeling; Molecular; Monitor; Morphology; Myelopoiesis; Newly Diagnosed; Outcome; Patients; Phase; Phase I/II Trial; Plasma; Population; Production; Refractory; Relapse; Remission Induction; Reporting; Research; Residual Neoplasm; Role; Safety; Severities; Stem cell transplant; Surface; Syndrome; T-Lymphocyte; Testing; Time; Toxic effect; Transplantation; Veno-Occlusive Disease; Work; Xenograft Model; acute myeloid leukemia cell; base; cellular transduction; chemotherapy; chimeric antigen receptor T cells; clinical development; design; experience; first-in-human; immunotherapy trials; improved; improved outcome; in vitro testing; in vivo; lentivirally transduced; leukemia; molecular marker; mortality; neurotoxicity; novel; novel therapeutic intervention; pediatric patients; phase I trial; phase III trial; pre-clinical; preclinical efficacy; preclinical study; proteogenomics; response; safety and feasibility; trial design; young adult

CD33 is a cell surface glycoprotein involved in normal myelopoiesis and is expressed on 80% of AML cells. Higher CD33 surface expression has been associated with inferior clinical outcomes in both children and adults with de novo AML. Several trials have demonstrated the safety and efficacy of targeting CD33 in both adult and pediatric AML. Most notable is the experience with gemtuzumab ozogamicin (GO) which has both single-agent activity and has been incorporated with intensive chemotherapy and is FDA approved for the treatment of AML. A recent phase 3 trial demonstrated improved event-free survival (EFS) in pediatric subjects with newly diagnosed AML when GO was incorporated into upfront therapy. Notable toxicities of GO include hepatotoxicity in the form of sinusoidal obstructive syndrome (SOS)/hepatic veno-occlusive disease (VOD). VOD/SOS after GO treatment is most commonly seen in the setting of hematopoietic cellular transplant (HCT). Although GO was removed from the commercial market by the FDA in 2010 based upon some data demonstrating lack of subject benefit, it was re-approved by the FDA in 2017 following new data demonstrating improved outcomes in subjects with AML. Given the outcomes of targeting CD33 with antibody-based therapeutics, CD33 remains an attractive antigen for immunotherapeutic targeting with CAR-modified T cells. Preclinical studies to date have demonstrated robust anti-leukemia activity of CD33 CAR T-cells in in vitro and in vivo AML model systems . We selected CD33 as an optimal target for a first-in-child AML CAR-T cell immunotherapy trial given its prevalent surface expression on AML blasts and the extensive clinical experience demonstrating safety and efficacy of CD33 targeting with gemtuzumab in children and young adults with AML. In preclinical studies used to inform this trial, six second-generation lentivirally-transduced CD33 CAR T-cells using three distinct CD33 ScFv constructs (gemtuzumab, lintuzumab, m195) each with one of two co-stimulatory domains CD3z and CD28 or 4-1BB was tested (manuscript in development). In vitro testing of CD33CARTs against multiple AML cell lines revealed that CD33/CD28zCAR-T cells consistently induced higher IL-2 and interferon-y production than did T cells transduced with CD33/4-1BB CAR constructs. Assessment of the six CD33 CAR T-cells in luciferase+ MOLM14 xenograft models and primary childhood AML patient derived xenograft (PDX) models further demonstrated potent in vivo anti-leukemia activity. Based upon superior preclinical efficacy in our tested models, the CD33.2/CD28z which incorporates the lintuzumab ScFv in the construct was selected and further optimized as the CD33 CAR T-cells clinical construct for this trial. Based on the pre-clinical efforts, a phase 1 trial was planned. This phase 1/2 trial aims to determine the safety and feasibility of anti-CD33 CAR expressing T cells (CD33CART) in children and adolescents/young adults (AYAs) with relapsed/refractory AML. The trial will be done in two phases: Phase 1 will determine the maximum tolerated dose of CD33CART cells using a 3+3 trial design. Phase 2 is an expansion phase designed to evaluate the rate of response to CD33CART. The CD33 CAR T-trial started enrollment in January 2020. This represents the first AML targeted approach in children with a highly collaborative clinical and translational efforts built into the infrastructure of the trial. We anticipate that several novel observations will emerge from this study. If the CAR construct is safe, feasible and effective, we will work on establishing an adult CD33 CAR T-trial. Secondary objectives for all subjects include: 1) To determine the feasibility of manufacturing CD33CART from subjects with AML and 2) To determine the feasibility of infusing CD33CART in subjects with AML. For the treatment population that receives CD33CART, secondary objectives include: 1) To determine the incidence and severity of CRS, sinusoidal occlusion syndrome (SOS), or other CD33CART related toxicities; 2) To estimate the overall survival, event-free survival, and treatment-related mortality at Day 28 post-CD33CART; 3) To determine the percentage of subjects treated with CD33CART who achieve morphologic remission (5% blasts in marrow) at Day 28 post-CD33CART cell infusion (for those in Phase I); 4) To determine the percentage of subjects treated with CD33CART who achieve molecular remission (for those with an identified molecular marker) at Day 28 post-CD33CART cell infusion; 5) To determine minimal residual disease (MRD) negativity by flow cytometry (0.1%) at Day 28 post-CD33CART cell infusion; and 6) To determine the percentage of subjects able to proceed to allogeneic hematopoietic stem cell transplantation following treatment with CD33CART. Post-HSCT outcomes, including engraftment and SOS will be closely monitored for. Exploratory objectives will be performed collaboratively and under the guidance of the multicenter local PIs and include: 1) To measure CD33CART remission induction by minimal residual disease assessments using research level NGS testing; 2) To correlate responses and CD33CART expansion with immunophenotypic CD33 surface expression, plasma concentrations of soluble CD33, and CD33 genotyping; 3) To quantify CD33CART expansion and in vivo persistence in blood and bone marrow of treated subjects at Day 28 post-CD33CART cell infusion and post-HCT; 4) To evaluate the AML surfacesome/proteogenomics; 5) To assess potential CD33CART-related neurotoxicity; and 6) To assess subject-reported adverse events prior to infusion and weekly in the month following CD33CART infusion

CD33 是一种参与正常骨髓生成​​的细胞表面糖蛋白，在 80% 的 AML 细胞上表达。较高的 CD33 表面表达与患有新发 AML 的儿童和成人较差的临床结果相关。多项试验已证明针对成人和儿童 AML 靶向 CD33 的安全性和有效性。最值得注意的是吉妥珠单抗奥佐米星 (GO) 的经验，该药物既具有单药活性，又与强化化疗相结合，并已被 FDA 批准用于治疗 AML。最近的一项 3 期试验表明，当将 GO 纳入前期治疗时，新诊断的 AML 儿科受试者的无事件生存期 (EFS) 得到改善。 GO 的显着毒性包括肝窦阻塞综合征 (SOS)/肝静脉闭塞病 (VOD) 形式的肝毒性。 GO 治疗后的 VOD/SOS 最常见于造血细胞移植 (HCT) 情况。尽管 GO 因一些数据显示缺乏受试者益处而于 2010 年被 FDA 从商业市场上撤下，但在新数据显示 AML 受试者的预后得到改善后，FDA 于 2017 年重新批准了 GO。鉴于使用基于抗体的疗法靶向 CD33 的结果，CD33 仍然是 CAR 修饰的 T 细胞免疫治疗靶向的有吸引力的抗原。迄今为止的临床前研究已证明 CD33 CAR T 细胞在体外和体内 AML 模型系统中具有强大的抗白血病活性。我们选择 CD33 作为首个儿童 AML CAR-T 细胞免疫治疗试验的最佳靶点，因为它在 AML 母细胞上普遍表达，并且广泛的临床经验证明吉妥珠单抗靶向 CD33 对患有 AML 的儿童和年轻人的安全性和有效性。在用于为该试验提供信息的临床前研究中，使用三种不同的 CD33 ScFv 构建体（gemtuzumab、lintuzumab、m195）的 6 个第二代慢病毒转导的 CD33 CAR T 细胞，每个构建体均具有两个共刺激结构域 CD3z 和 CD28 或 4-1BB 之一已经过测试（手稿正在开发中）。针对多种 AML 细胞系的 CD33CART 体外测试表明，与用 CD33/4-1BB CAR 构建体转导的 T 细胞相比，CD33/CD28zCAR-T 细胞始终诱导更高的 IL-2 和干扰素 y 产生。对荧光素酶+ MOLM14 异种移植模型和儿童 AML 患者衍生异种移植 (PDX) 模型中的 6 个 CD33 CAR T 细胞的评估进一步证明了有效的体内抗白血病活性。基于我们测试的模型中优异的临床前疗效，选择并进一步优化了构建体中包含林妥珠单抗 ScFv 的 CD33.2/CD28z 作为本试验的 CD33 CAR T 细胞临床构建体。根据临床前工作，计划进行一期试验。这项 1/2 期试验旨在确定抗 CD33 CAR 表达 T 细胞 (CD33CART) 在患有复发/难治性 AML 的儿童和青少年/年轻人 (AYA) 中的安全性和可行性。该试验将分两个阶段进行：第一阶段将采用 3+3 试验设计确定 CD33CART 细胞的最大耐受剂量。第 2 阶段是扩展阶段，旨在评估 CD33CART 的响应率。 CD33 CAR T 试验于 2020 年 1 月开始招募。这是第一个针对儿童的 AML 靶向方法，试验基础设施中内置了高度协作的临床和转化工作。我们预计这项研究将会出现一些新的观察结果。如果CAR构建安全、可行、有效，我们将致力于建立成人CD33 CAR T试验。所有受试者的次要目标包括：1) 确定从患有 AML 的受试者中制造 CD33CART 的可行性，以及 2) 确定在患有 AML 的受试者中输注 CD33CART 的可行性。对于接受 CD33CART 的治疗人群，次要目标包括： 1) 确定 CRS、正窦闭塞综合征 (SOS) 或其他 CD33CART 相关毒性的发生率和严重程度； 2) 估计CD33CART后第28天的总生存期、无事件生存期和治疗相关死亡率； 3) 确定在 CD33CART 细胞输注后第 28 天（对于 I 期患者），接受 CD33CART 治疗的受试者达到形态学缓解（骨髓中原始细胞为 5%）的百分比； 4) 确定接受 CD33CART 治疗的受试者在 CD33CART 细胞输注后第 28 天实现分子缓解（对于那些具有已识别分子标记的受试者）的百分比； 5) 在CD33CART细胞输注后第28天通过流式细胞术(0.1%)确定微小残留病(MRD)阴性； 6) 确定在用CD33CART治疗后能够进行同种异体造血干细胞移植的受试者的百分比。将密切监测 HSCT 后的结果，包括植入和 SOS。探索性目标将在多中心当地 PI 的指导下协作执行，包括： 1) 使用研究级 NGS 测试通过微小残留病评估来测量 CD33CART 缓解诱导； 2) 将反应和 CD33CART 扩增与免疫表型 CD33 表面表达、可溶性 CD33 血浆浓度和 CD33 基因分型关联起来； 3) 量化 CD33CART 细胞输注后和 HCT 后第 28 天时治疗受试者血液和骨髓中的 CD33CART 扩增和体内持久性； 4) 评估AML表面体/蛋白质组学； 5) 评估潜在的CD33CART相关神经毒性； 6) 在输注前和输注 CD33CART 输注后每月每周评估受试者报告的不良事件