Targeting Neuroblastoma with armed T cells

用武装 T 细胞靶向神经母细胞瘤

• 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
• 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

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)：儿童第四期神经母细胞瘤(NB)是一种18个月大的侵袭性疾病，在成功的诱导治疗后经常复发。尽管采取了强化治疗方案，但存活率是不可接受的。表达于NB的神经节苷脂GD2是抗体依赖性细胞毒作用的理想靶点。抗GD2单抗(MAb)免疫治疗IV期微小残留病患者显著延长了无进展生存期(PFS)和增加了总生存期(OS)，但这些IV期患者中37%在2年内复发。遗憾的是，抗GD2单抗的临床疗效受到毒副作用的限制。需要新颖和创新的方法，在不增加毒性的情况下增加抗肿瘤活性。我们最近发现，用小鼠抗CD3x抗GD2双特异性抗体(抗CD3x抗GD2双特异性抗体)和抗CD3x抗GD2(人源化3F8的人源化版本)武装的抗CD3激活的T细胞(ATC)在体外和体内对NB细胞的杀伤活性都有所增强。在输注hu3F8bi武装ATC的NB异种移植模型中，肿瘤生长延迟，存活率提高。在转移性乳腺癌的I期临床试验中，多次静脉滴注抗CD3x抗Her2双特异性抗体(Her2bi)，联合小剂量IL-2和粒-巨噬细胞集落刺激因子(GM-CSF)治疗IV期转移性乳腺癌0-3+Her2阳性乳腺癌患者是安全的，诱导的抗乳腺癌细胞毒作用、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15周后，在22例可评估的患者中，1例肝转移患者和12例稳定患者的中位OS为36个月，1例部分缓解。我们推测，携带hu3F8bi的ATC将增强抗Nb的细胞毒作用，并针对其自身的Nb抗原接种PTS。为了验证这一假设，我们提出了以下具体目标：1)提交IND，生产GD2Bi(Hu3F8bi)，并在复发/难治性NB和GD2+肿瘤患者中执行I期剂量升级方案，以确定hu3F8bi武装ATC在标准3+3剂量升级方案中的MTD，该方案包括40、80和160×106个/kg/输注剂量水平；2)在22名患者中进行II期临床试验，以探索并确认hu3F8bi武装ATC的MTD；3)连续监测针对NB的免疫反应(细胞毒性，干扰素？(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向肿瘤的转运；以及5)在10名PET/CT可测量软组织和骨骼病变的患者中进行探索性研究，以评估武装ATC的转运。如果成功，这些研究将改变NB的治疗模式，细胞毒性不仅可以减少微小的残留病，还可以为患者接种针对自己肿瘤的疫苗，从而显著改善PFS和OS。