Targeting Neuroblastoma with armed T cells

用武装 T 细胞靶向神经母细胞瘤

基本信息

批准号：
8760348
负责人：
NAI-KONG V CHEUNG
金额：
$ 80.25万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-12 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8760348
关键词：
Adverse effects Age-Months Antibodies Antigen Targeting Antigens Biopsy Bispecific Antibodies Blood Bone Marrow Breast CD3 Antigens Cell Line Cells Cephalic Child Chimeric Proteins Clinical Clinical Research Clinical Treatment Clinical Trials Cytolysis Cytotoxic T-Lymphocytes Disease Dose ERBB2 gene Evaluable Disease Exhibits Ganglioside GD2 Granulocyte-Macrophage Colony-Stimulating Factor Granzyme High Dose Chemotherapy Human Image Immune Immune response Immunotherapy In Vitro Infusion procedures Interferons Interleukin-12 Interleukin-2 Investigational Drugs Lesion Maximum Tolerated Dose Measurable Mediating Metastatic Neoplasm to the Liver Monitor Monoclonal Antibodies Muromonab-CD3 Mus Neoadjuvant Therapy Neuroblastoma Outcome PET/CT scan Participant Patients Pattern Pediatric Neoplasm Peripheral Blood Mononuclear Cell Phase Phase I Clinical Trials Phase I/II Trial Phase II Clinical Trials Phenotype Progression-Free Survivals Protocols documentation Recurrence Refractory Relapse Residual Neoplasm Safety Serum Stable Disease Staging Staining method Stains Stem cell transplant Survival Rate T-Lymphocyte Testing Toxic effect Treatment Protocols Vaccinated Woman Xenograft Model Xenograft procedure antibody-dependent cell cytotoxicity arm base chemotherapy clinical efficacy cohort cytokine cytotoxicity fluorodeoxyglucose positron emission tomography high risk improved in vivo innovation killings malignant breast neoplasm monoclonal antibody 3F8 mouse model neuroblastoma cell novel osteosarcoma partial response perforin preclinical study public health relevance response skeletal soft tissue trafficking tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Stage IV neuroblastoma (NB) in children >18 months of age is an aggressive disease that often recurs after successful induction therapy. Despite intensive treatment regimens, survival rates are unacceptable. Ganglioside GD2 expressed on NB is an ideal target for antibody-dependent cellular cytotoxicity. Anti-GD2 monoclonal antibody (mAb) immunotherapy in stage IV patients with minimal residual disease significantly prolongs progression free survival (PFS) and increased overall survival (OS); however, 37% of these stage IV patients relapse within 2 years. Unfortunately, clinical efficacy of anti-GD2 mAbs has been limited by toxicities. There is a need for novel and innovative approaches that increase anti-tumor activity without increasing toxicities. We recently showed that anti-CD3 activated T cells (ATC) armed with murine GD2Bi (anti-CD3 x anti-GD2 bispecific antibody) and ATC armed with anti-CD3 x anti-GD2 (humanized version of 3F8) exhibit enhanced in vitro and in vivo potency against NB cells. Delayed tumor growth and improved survival was seen in a NB xenograft model following infusions of hu3F8Bi armed ATC. In a phase I clinical trial for metastatic breast, multiple infusions of anti-CD3 x anti-Her2 bispecific antibody (Her2Bi) armed ATC in combination with low dose IL-2 and granulocyte-macrophage colony stimulating factor (GM-CSF) in women with heavily pretreated stage IV metastatic 0-3+ Her2 positive breast cancer were safe, induced anti-breast cancer cytotoxicity, anti-breast cancer antibodies, serum Th1 cytokine patterns, and IL-12 levels. Surprisingly, median OS was 36 months with 1 very good partial response in a patient with liver metastases and 12 patients with stable disease out of 22 evaluable pts at 15 weeks after starting immunotherapy. We hypothesized that hu3F8Bi armed ATC will enhance anti-NB cytotoxicity and vaccinate the pts against their own NB antigens. To test this hypothesis, we propose the following specific aims: 1) Submit a IND, produce GD2Bi (hu3F8Bi), and perform a phase I dose-escalation protocol in patients with recurrent/refractory NB and GD2+ tumors to determine the MTD for hu3F8Bi armed ATC infused twice a week for 8 infusions in combination with daily low dose IL-2 (300,000 IU/m2/day) in a standard 3 + 3 dose escalation schema with 40, 80, and 160 x 106 cells/kg/infusion dose levels; 2) Conduct a phase II clinical trial in 22 patients to explore efficacy and confirm the toxicity profile of hu3F8Bi armed ATC using the MTD; 3) Sequentially monitor immune responses directed at NB (cytotoxicity, IFN? EliSpots), phenotyping, cytokine patterns, and antibodies to NB; 4) Assess survival and persistence of armed ATC in the blood and tumor biopsies to confirm trafficking of armed ATC to tumor; and 5) Conduct an exploratory study of [18F] FDG PET/CT in 10 selected patients with PET/CT measurable soft tissue and skeletal lesions to evaluate trafficking of armed ATC. If successful, these studies will provide a shift in the treatment paradigm for NB where cytotoxicity would not only reduce minimal residual disease but also "vaccinate" the patients against their own tumor resulting in significant improvement in PFS and OS.

描述（由申请人提供）：18 个月以上儿童的 IV 期神经母细胞瘤 (NB) 是一种侵袭性疾病，在成功诱导治疗后经常复发。尽管采用强化治疗方案，存活率仍令人无法接受。 NB 上表达的神经节苷脂 GD2 是抗体依赖性细胞毒性的理想靶标。抗GD2单克隆抗体（mAb）免疫治疗IV期微小残留病患者可显着延长无进展生存期（PFS）并提高总生存期（OS）；然而，这些 IV 期患者中有 37% 在 2 年内复发。不幸的是，抗 GD2 mAb 的临床疗效受到毒性的限制。需要新的和创新的方法来增加抗肿瘤活性而不增加毒性。我们最近表明，配备鼠GD2Bi（抗CD3 x 抗GD2双特异性抗体）的抗CD3激活T细胞（ATC）和配备抗CD3 x抗GD2（3F8人源化版本）的ATC在体外和体外表现出增强的能力。体内对 NB 细胞的效力。在输注 hu3F8Bi 武装 ATC 后，在 NB 异种移植模型中观察到肿瘤生长延迟和生存率提高。在一项针对转移性乳腺的 I 期临床试验中，对患有转移性乳腺疾病的女性多次输注抗 CD3 x 抗 Her2 双特异性抗体 (Her2Bi) 武装 ATC 联合低剂量 IL-2 和粒细胞巨噬细胞集落刺激因子 (GM-CSF)经过大量预处理的 IV 期转移性 0-3+ Her2 阳性乳腺癌是安全的，可诱导抗乳腺癌细胞毒性、抗乳腺癌抗体、血清 Th1 细胞因子模式和IL-12 水平。令人惊讶的是，在开始免疫治疗后 15 周时，22 名可评估患者中，中位 OS 为 36 个月，其中 1 名肝转移患者和 12 名疾病稳定患者出现了非常好的部分缓解。我们假设 hu3F8Bi 武装的 ATC 将增强抗 NB 细胞毒性并针对患者自身的 NB 抗原进行疫苗接种。为了检验这一假设，我们提出以下具体目标：1) 提交 IND，生产 GD2Bi (hu3F8Bi)，并对复发/难治性 NB 和 GD2+ 肿瘤患者执行 I 期剂量递增方案，以确定 hu3F8Bi 武装的 MTD ATC 每周输注两次，共 8 次输注，并与每日低剂量 IL-2（300,000 IU/m2/天）联合使用，标准剂量为3 + 3 剂量递增方案，40、80 和 160 x 106 细胞/kg/输注剂量水平； 2）对22名患者进行II期临床试验，利用MTD探索hu3F8Bi武装ATC的疗效并确认毒性特征； 3) 依次监测针对 NB 的免疫反应（细胞毒性、IFN? EliSpots）、表型、细胞因子模式和 NB 抗体； 4) 评估武装ATC在血液和肿瘤活检中的存活率和持久性，以确认武装ATC是否被贩运至肿瘤； 5) 对 10 名选定的 PET/CT 可测量软组织和骨骼病变的患者进行 [18F] FDG PET/CT 探索性研究，以评估武装 ATC 的贩运。如果成功，这些研究将为 NB 的治疗模式带来转变，其中细胞毒性不仅可以减少微小残留病，还可以为患者“接种疫苗”以抵抗其自身的肿瘤，从而显着改善 PFS 和 OS。