Targeting Neuroblastoma with armed T cells

用武装 T 细胞靶向神经母细胞瘤

• 批准号: 9325268
• 负责人: NAI-KONG V CHEUNG
• 金额: $ 82.29万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325268
• 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; Health; 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; improved outcome; in vivo; innovation; killings; malignant breast neoplasm; monoclonal antibody 3F8; mouse model; neuroblastoma cell; novel; osteosarcoma; partial response; perforin; preclinical study; relapse patients; response; skeletal; soft tissue; targeted treatment; trafficking; tumor; tumor growth; tumor progression

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）：年龄>18个月的儿童中的IV期神经母细胞瘤（NB）是一种侵袭性疾病，通常在成功的诱导治疗后复发。尽管采取了强化治疗方案，但存活率仍不可接受。神经节苷脂GD 2在NB上的表达是抗体依赖性细胞毒性的理想靶点。抗GD 2单克隆抗体（mAb）免疫治疗IV期微小残留病患者显著延长无进展生存期（PFS）并增加总生存期（OS）;然而，这些IV期患者中有37%在2年内复发。不幸的是，抗GD 2 mAb的临床疗效受到毒性的限制。需要增加抗肿瘤活性而不增加毒性的新颖和创新的方法。我们最近显示，装备有鼠GD 2Bi（抗-CD 3 X抗-GD 2双特异性抗体）的抗-CD 3活化的T细胞（ATC）和装备有抗-CD 3 X抗-GD 2（3F 8的人源化版本）的ATC表现出针对NB细胞的增强的体外和体内效力。在输注hu 3F 8Bi武装的ATC后，在NB异种移植物模型中观察到延迟的肿瘤生长和改善的存活。在转移性乳腺癌的I期临床试验中，在患有重度预治疗的IV期转移性0-3+ Her 2阳性乳腺癌的女性中多次输注装备有抗CD 3 X抗Her 2双特异性抗体（Her 2Bi）的ATC与低剂量IL-2和粒细胞-巨噬细胞集落刺激因子（GM-CSF）的组合是安全的，诱导抗乳腺癌细胞毒性，抗乳腺癌抗体，血清Th 1细胞因子模式和IL-12水平。令人惊讶的是，中位OS为36个月，在开始免疫治疗后15周时，在患有肝转移的患者中有1例非常好的部分缓解，在22名可评估患者中有12名患者病情稳定。我们假设hu 3F 8Bi武装的ATC将增强抗NB细胞毒性并针对其自身的NB抗原接种患者。为了检验这一假设，我们提出了以下具体目标：1）提交IND，产生GD 2Bi（hu 3F 8Bi），并在患有复发性/难治性NB和GD 2+肿瘤的患者中进行I期剂量递增方案，以确定每周两次输注持续8次输注的hu 3F 8Bi武装的ATC与每日低剂量IL-2组合的MTD 2）在22名患者中进行II期临床试验，以使用MTD探索hu 3F 8Bi武装的ATC的功效并确认其毒性特征; 3）连续监测针对NB的免疫应答（细胞毒性、IFN？EliSpots）、表型、细胞因子模式和NB抗体; 4）评估血液和肿瘤活检中武装ATC的存活和持久性，以确认武装ATC向肿瘤的运输;和5）在10名具有PET/CT可测量的软组织和骨骼病变的选定患者中进行[18F] FDG PET/CT的探索性研究，以评估武装ATC的运输。如果成功，这些研究将为NB的治疗模式提供转变，其中细胞毒性不仅可以减少微小残留疾病，还可以为患者接种针对其自身肿瘤的“疫苗”，从而显著改善PFS和OS。