INTRATUMORAL INTERFERON GAMMA DURING VACCINATION IN METASTATIC MELANOMA

转移性黑色素瘤疫苗接种期间的瘤内干扰素γ

• 批准号: 8167196
• 负责人: Craig Lee Slingluff
• 金额: $ 1.87万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167196
• 关键词: Adjuvant; Adjuvant Therapy; Antibodies; CD8B1 gene; CXCL10 gene; CXCL11 gene; CXCL9 gene; CXCR3 gene; Cell Therapy; Clinical; Computer Retrieval of Information on Scientific Projects Database; Disease; Dose; Eligibility Determination; FDA approved; Funding; Goals; Grant; Hand; Immunity; Immunologics; Immunotherapy; In complete remission; Inflammation; Institution; Interferon Type II; Interferon gamma 1b; Interferon-alpha; Interferons; Interleukin-2; Ligands; Measurable Disease; Melanoma Vaccine; Metastatic Melanoma; Outcome; Participant; Patients; Peptide Vaccines; Phase III Clinical Trials; Protocols documentation; Recombinant Interferon-gamma; Recruitment Activity; Reporting; Research; Research Personnel; Resected; Resources; Role; Safety; Site; Source; Subgroup; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Tumor Antigens; United States National Institutes of Health; Vaccination; Vaccine Therapy; Vaccines; Work; advanced disease; chemokine; chemokine receptor; experience; high risk; improved; melanoma; response; trafficking; tumor; Adjuvant; Adjuvant Therapy; Antibodies; CD8B1 gene; CXCL10 gene; CXCL11 gene; CXCL9 gene; CXCR3 gene; Cell Therapy; Clinical; Computer Retrieval of Information on Scientific Projects Database; Disease; Dose; Eligibility Determination; FDA approved; Funding; Goals; Grant; Hand; Immunity; Immunologics; Immunotherapy; In complete remission; Inflammation; Institution; Interferon Type II; Interferon gamma 1b; Interferon-alpha; Interferons; Interleukin-2; Ligands; Measurable Disease; Melanoma Vaccine; Metastatic Melanoma; Outcome; Participant; Patients; Peptide Vaccines; Phase III Clinical Trials; Protocols documentation; Recombinant Interferon-gamma; Recruitment Activity; Reporting; Research; Research Personnel; Resected; Resources; Role; Safety; Site; Source; Subgroup; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Tumor Antigens; United States National Institutes of Health; Vaccination; Vaccine Therapy; Vaccines; Work; advanced disease; chemokine; chemokine receptor; experience; high risk; improved; melanoma; response; trafficking; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Melanoma vaccines have been associated with major regressions in 3-6% of patients with advanced measurable disease. This provides proof-of-principle of the potential for clinical benefit with melanoma vaccines. However, negative results have been obtained in several phase III clinical trials with some melanoma vaccines. On the other hand, subgroup analyses from at least two of those trials suggest the possibility of benefit in participant subsets. The UVA experience with multipeptide vaccines includes the induction of antitumor immunity in a majority of participants, clinical outcomes for participants treated in the adjuvant setting that exceed predicted outcomes, and clinical tumor regressions in 5-10% of participants treated with vaccines in the setting of advanced metastatic disease. Dramatic regressions of melanoma have been induced with several other immune therapies, including high-dose interleukin-2 (FDA approved for advanced melanoma), anti-CTLA4 antibody, and adoptive T cell therapy, with reported objective response rates of 17%, 13%, and 51%, respectively, and with complete response (CR) rates in the range of 4-7%. Results with these therapies provide further proof-of-principle for the therapeutic potential of immune therapy in melanoma. Unfortunately, the toxicities for all three therapies limit participant eligibility; so less toxic immune therapies with vaccines have a role, especially in the adjuvant setting. The only FDA-approved adjuvant therapy for patients with resected high-risk melanoma is high-dose, systemic interferon alpha. However, the most recent pooled analysis of interferon alpha therapy highlights the questionable survival advantage even of that therapy, for patients in the adjuvant setting. Thus, there is a critical need for additional new therapies for melanoma, both for adjuvant therapy of high-risk resected melanoma and for therapy of patients who are not candidates for, or fail, other therapies in the setting of advanced disease. It is generally agreed that one mechanism to improve the immunologic outcomes of vaccine therapy is to optimize T cell trafficking to the tumor site. CXCR3 is the chemokine receptor on T cells which directs them to sites of inflammation by following the chemokine gradient. The ligands for CXCR3 (CXCL9 (MIG), CXCL10 (IP-10) and CXCL11 (I-TAC)) are known to be induced by interferon gamma (IFN- )13,14. This protocol proposes administering peptide vaccine to activate tumor antigen-specific CD8+ T cells expressing CXCR3, followed by intratumoral interferon gamma to increase CXCR3 ligands (CXCL9-11) at the tumor site and recruit the CXCR3+ T cells. While there is also the potential for clinical benefit for participants receiving the vaccine in combination with intratumoral interferon gamma (Actimmune, interferon gamma-1b), this current study is not powered to test clinical outcomes. The primary goals of the proposed work are to assess the safety of the combination of peptide vaccine and intratumoral interferon gamma and to assess the immunologic outcomes at the tumor site.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 黑色素瘤疫苗与3-6％的晚期可测量疾病患者的重大回归有关。 这提供了黑色素瘤疫苗临床益处的原理证明。 但是，在一些黑色素瘤疫苗的几项III期临床试验中，已经获得了负结果。 另一方面，其中至少两个试验的亚组分析表明参与者子集有利益。 多肽疫苗的UVA经验包括大多数参与者的抗肿瘤免疫，在辅助环境中接受治疗的参与者的临床结果超过预测的结果，以及在晚期转移性疾病的情况下用疫苗治疗的5-10％的参与者中的临床肿瘤回归。 黑色素瘤的戏剧性回归已被其他几种免疫疗法诱导，包括高剂量白介素-2（批准用于晚期黑色素瘤），抗CTLA4抗体和收养T细胞疗法，报告的客观反应率分别为17％，13％和51％，并且范围为4--7％。 这些疗法的结果为黑色素瘤免疫治疗的治疗潜力提供了进一步的原则证明。 不幸的是，所有三种疗法的毒性都限制了参与者的资格；因此，使用疫苗的毒性免疫疗法较少，尤其是在辅助环境中。 唯一针对切除的高风险黑色素瘤患者的FDA批准辅助治疗是高剂量的全身干扰素α。 但是，对于辅助设置中的患者，对干扰素α疗法的最新汇总分析甚至突出了该疗法的可疑生存优势。 因此，对于黑色素瘤的辅助治疗，对黑色素瘤的辅助治疗以及对不候选或失败的其他疗法在晚期疾病的疗法的疗法的辅助治疗至关重要。 人们普遍认为，提高疫苗疗法免疫结局的一种机制是优化T细胞运输到肿瘤部位。 CXCR3是T细胞上的趋化因子受体，它通过跟随趋化因子梯度将其引导到炎症部位。 已知CXCR3（CXCL9（MIG），CXCL10（IP-10）和CXCL11（I-TAC））的配体已被Interferon Gamma（IFN-）13,14诱导。 该方案提出了施用肽疫苗来激活表达CXCR3的肿瘤抗原特异性CD8+ T细胞，然后进行肿瘤内干扰素伽马γ在肿瘤部位增加CXCR3配体（CXCL9-11）并募集CXCR3+ T细胞。 尽管对于接受疫苗的参与者以及肿瘤内干扰素伽马（Actimmune，Interferon Gamma-1b）的参与者也有可能获得临床益处，但这项当前的研究无权测试临床结果。 拟议工作的主要目标是评估肽疫苗和肿瘤内干扰素伽马的组合安全性，并评估肿瘤部位的免疫结局。