POLYVALENT VACCINE IN IL-2+GM-CSF LIPOSOMES FOR MELANOMA

IL-2 GM-CSF 脂质体中的多价疫苗用于治疗黑色素瘤

• 批准号: 6522757
• 负责人: JEAN-CLAUDE BYSTRYN
• 金额: $ 34.96万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-12 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6522757
• 关键词: antitumor antibody; colony stimulating factor; guinea pigs; human subject; human therapy evaluation; interleukin 2; laboratory mouse; liposomes; melanoma; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; nonhuman therapy evaluation; patient oriented research; tumor antigens; vaccine development; western blottings

Our goal is to develop a potent adjuvant that can strongly, but safely, boost the immunogenicity of cancer vaccines. The proposal is based on recent observations that IL-2 and GM-CSF can individually increase the immunogenicity of vaccines, and that the adjuvant activity of each cytokine is markedly increased by co-encapsulating the cytokine into liposomes together with the vaccine. As each cytokine upregulates vaccine immunogenicity by different mechanisms, the combination of both cytokines should result in a particularly potent adjuvant. To test this hypothesis, we propose to conduct a randomized phase II trial to examine: 1) Whether IL-2+GM-CSF co-encapsulated into liposomes together with a melanoma vaccine can increase vaccine-induced cellular immune responses more strongly than either cytokine alone. Patients with resected AJCC stage III melanoma who are HLA-A2(+) will be randomized to treatment with a polyvalent, shed melanoma antigen vaccine encapsulated into lipsomes together with IL-2 or GM-CSF, or with both cytokines. The magnitude of vaccine-induced CD8+ T cell responses to A-2 restricted peptides derived from MAGE-3, MART-1, gp100, tyrosinase and TRP-2 will be measured by ELISPOT at baseline and at fixed intervals following immunization. 2) Whether IL-2+ GM-CSF lipisomes can enhance vaccine-induced antibody responses more strongly than either cytokine alone: Vaccine-induced antibody responses in the 3 groups of patients will be measured to individual melanoma antigens by Western immunoblotting. 3)The safety of this treatment/ Side effects will be followed by standard procedures. Major strengths of this proposal are that we have already demonstrated that IL-2 liposomes and GM-CSF liposomes are individually potent vaccine adjuvants in humans, that we have determined the optimal doses of each cytokine that maximally enhance vaccine-induced immune responses when encapsulated into lipsomes, that we have developed assays that are sufficiently sensitive to measure vaccine-induced CD8+ T cell and antibody responses to individual melanoma antigens, and that the vaccine contains multiple melanoma antigens so that the adjuvant activity of IL-2 + GM-CSF liposomes with different antigens can be evaluated. Successful completion of this work will provide a new method to increase the effectiveness of melanoma vaccines, and may lead to an improved treatment for the primary and secondary prevention of this cancer. More broadly, it may provide a general method of potentiating the immunogenicity of vaccines against other cancers and to infectious diseases.

我们的目标是开发一种有效的佐剂，可以强力但安全地增强癌症疫苗的免疫原性。 该提议基于最近的观察，即IL-2和GM-CSF可以单独增加疫苗的免疫原性，并且通过将细胞因子与疫苗共同封装到脂质体中，每种细胞因子的佐剂活性显着增加。 由于每种细胞因子通过不同的机制上调疫苗的免疫原性，因此两种细胞因子的组合应该产生特别有效的佐剂。 为了检验这一假设，我们建议进行一项随机 II 期试验来检查：1）将 IL-2+GM-CSF 与黑色素瘤疫苗一起共同封装到脂质体中是否可以比单独使用任何一种细胞因子更强烈地增加疫苗诱导的细胞免疫反应。 HLA-A2(+) 的 AJCC III 期黑色素瘤切除患者将被随机分配接受封装在脂质体中的多价、脱落黑色素瘤抗原疫苗与 IL-2 或 GM-CSF 或与两种细胞因子一起治疗。 疫苗诱导的 CD8+ T 细胞对源自 MAGE-3、MART-1、gp100、酪氨酸酶和 TRP-2 的 A-2 限制性肽的反应强度将通过 ELISPOT 在基线和免疫后的固定时间间隔进行测量。 2) IL-2+ GM-CSF脂质体是否比单独使用任一细胞因子更能增强疫苗诱导的抗体反应：将通过Western免疫印迹法测量3组患者中针对个体黑色素瘤抗原的疫苗诱导的抗体反应。 3）该治疗的安全性/副作用将遵循标准程序。该提案的主要优点是，我们已经证明，IL-2 脂质体和 GM-CSF 脂质体在人类中分别是有效的疫苗佐剂，我们已经确定了每种细胞因子的最佳剂量，当封装到脂质体中时，可以最大程度地增强疫苗诱导的免疫反应，我们已经开发了足够灵敏的测定法来测量疫苗诱导的 CD8+ T 细胞和 抗体对单个黑色素瘤抗原的反应，并且疫苗含有多种黑色素瘤抗原，因此可以评估具有不同抗原的IL-2 + GM-CSF脂质体的佐剂活性。 这项工作的成功完成将为提高黑色素瘤疫苗的有效性提供一种新方法，并可能改善这种癌症一级和二级预防的治疗方法。 更广泛地说，它可能提供一种增强疫苗针对其他癌症和传染病的免疫原性的通用方法。