CTLA-4 Blockade in GM-CSF Vaccinated Patients

GM-CSF 疫苗接种患者中的 CTLA-4 阻断

• 批准号: 6740055
• 负责人: FRANK S HODI
• 金额: $ 36.47万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-22 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6740055
• 关键词: acute myelogenous leukemia; clinical research; clinical trial phase I; colony stimulating factor; combination cancer therapy; gene therapy; human subject; human therapy evaluation; melanoma; monoclonal antibody; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; nonsmall cell lung cancer; ovary neoplasms; patient oriented research

DESCRIPTION (provided by applicant): Despite convincing evidence for a host's ability to mount immune responses to a large number of cancer-associated gene products, most patients with advanced malignancies still succumb to their disease. One means by which a host may fail to adequately mount an effective anti-tumor immune response is ineffective priming of the immune system in tumor antigen presentation. We have investigated a strategy to augment antigen presentation involving vaccination with autologous, irradiated tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF). A majority of metastatic lesions resected after vaccination of patients with metastatic melanoma and non-small cell lung cancer showed brisk or focal T lymphocyte and plasma cell infiltrates with tumor necrosis. While significant numbers of patients achieved durable clinical responses to this vaccination strategy, most eventually develop progressive disease. One mechanism that may limit the therapeutic potency of cancer vaccines is the attenuation of T cell function by CTLA-4. In murine models, concurrent administration of CTLA4 antibody blockade with vaccination with irradiated, GM-CSF secreting tumor cells increases the rejection of poorly immunogenic tumors. To gain a preliminary assessment of the biologic activity of CTLA4 blockade in humans, we treated previously vaccinated patients with metastatic melanoma and ovarian carcinoma with the humanized monoclonal antibody MDX-CTLA4. MDX-CTLA4 stimulated extensive tumor necrosis with lymphocyte and granulocyte infiltrates in three metastatic melanoma patients and the reduction or stabilization of CA-125 levels in two metastatic ovarian carcinoma patients previously vaccinated with irradiated, autologous GM-CSF secreting tumor cells. Potential synergies of MDX-CTLA4 and GM-CSF-based vaccines need further exploration. Currently, we are performing phase I trials of GM-CSF based vaccines using lethally irradiated, autologous tumor cells in patients with metastatic melanoma, metastatic non-small call lung cancer, advanced ovarian cancer, and acute myelogenous leukemia (AML)/advanced myelodysplasia. This offers the unique opportunity to further evaluate the safety and efficacy of this combination therapy in a variety of malignancies, as well as explore antigen-specific changes in T cell responses as a function on CTLA-4 blockade.

描述（由申请人提供）：尽管有令人信服的证据表明宿主有能力对大量癌症相关基因产物产生免疫应答，但大多数晚期恶性肿瘤患者仍然死于疾病。宿主可能无法充分启动有效的抗肿瘤免疫应答的一种方式是免疫系统在肿瘤抗原呈递中的无效引发。我们已经研究了一种策略，以增加抗原呈递，涉及疫苗接种自体，照射肿瘤细胞工程分泌粒细胞-巨噬细胞集落刺激因子（GM-CSF）。大部分转移性黑色素瘤和非小细胞肺癌患者接种疫苗后切除的转移灶显示活跃或局灶性T淋巴细胞和浆细胞浸润伴肿瘤坏死。虽然大量患者对这种疫苗接种策略实现了持久的临床应答，但大多数最终发展为进行性疾病。可能限制癌症疫苗的治疗效力的一种机制是CTLA-4对T细胞功能的减弱。在鼠模型中，CTLA 4抗体阻断与用经照射的分泌GM-CSF的肿瘤细胞接种疫苗的同时施用增加了免疫原性差的肿瘤的排斥。为了获得CTLA 4阻断在人类中的生物活性的初步评估，我们用人源化单克隆抗体MDX-CTLA 4治疗先前接种疫苗的转移性黑素瘤和卵巢癌患者。MDX-CTLA 4在3名转移性黑色素瘤患者中刺激了淋巴细胞和粒细胞浸润的广泛肿瘤坏死，在2名先前接种过放射性自体GM-CSF分泌肿瘤细胞的转移性卵巢癌患者中刺激了CA-125水平的降低或稳定。MDX-CTLA 4和GM-CSF疫苗的潜在协同作用需要进一步探索。目前，我们正在转移性黑色素瘤、转移性非小细胞肺癌、晚期卵巢癌和急性髓性白血病（AML）/晚期骨髓增生异常患者中进行基于GM-CSF的疫苗的I期试验。这提供了独特的机会，以进一步评估这种组合疗法在各种恶性肿瘤中的安全性和有效性，以及探索T细胞应答中的抗原特异性变化作为CTLA-4阻断的函数。