CTLA-4 Blockade in GM-CSF Vaccinated Patients

描述（由申请人提供）：尽管有令人信服的证据表明宿主能够对大量癌症相关基因产物产生免疫反应，但大多数晚期恶性肿瘤患者仍然死于疾病。宿主可能无法充分建立有效的抗肿瘤免疫应答的一种手段是在肿瘤抗原呈递中免疫系统的无效启动。我们研究了一种增加抗原呈递的策略，包括用自体辐照肿瘤细胞接种疫苗，使其分泌粒细胞-巨噬细胞集落刺激因子（GM-CSF）。大多数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性病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取得了持久的临床反应，但大多数患者最终发展为进行性疾病。一种可能限制癌症疫苗治疗效力的机制是CTLA-4对T细胞功能的衰减。在小鼠模型中，CTLA4抗体阻断剂与放射的GM-CSF分泌肿瘤细胞接种同时施用，增加了对免疫原性差的肿瘤的排斥反应。为了初步评估CTLA4阻断剂在人体内的生物活性，我们使用人源化单克隆抗体MDX-CTLA4治疗先前接种过转移性黑色素瘤和卵巢癌的患者。MDX-CTLA4在3例转移性黑色素瘤患者中刺激了广泛的肿瘤坏死，伴有淋巴细胞和粒细胞浸润，在2例先前接种过辐照的自体GM-CSF分泌肿瘤细胞的转移性卵巢癌患者中降低或稳定了CA-125水平。MDX-CTLA4和gm - csf疫苗的潜在协同作用有待进一步探索。目前，我们正在对转移性黑色素瘤、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进行基于GM-CSF的疫苗的I期试验。这为进一步评估这种联合疗法在多种恶性肿瘤中的安全性和有效性，以及探索CTLA-4阻断作用下T细胞反应中抗原特异性变化提供了独特的机会。

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.