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

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 黑色素瘤疫苗与 3-6% 晚期可测量疾病患者的严重消退有关。 这为黑色素瘤疫苗的临床益处潜力提供了原理证明。 然而，一些黑色素瘤疫苗的多项 III 期临床试验却获得了阴性结果。 另一方面，至少其中两项试验的亚组分析表明，参与者子集可能受益。 UVA 使用多肽疫苗的经验包括在大多数参与者中诱导抗肿瘤免疫，在辅助治疗中治疗的参与者的临床结果超出预期结果，以及在晚期转移性疾病的情况下接受疫苗治疗的 5-10% 的参与者的临床肿瘤消退。 其他几种免疫疗法已诱导黑色素瘤显着消退，包括高剂量白介素-2（FDA 批准用于晚期黑色素瘤）、抗 CTLA4 抗体和过继性 T 细胞疗法，报告的客观缓解率分别为 17%、13% 和 51%，完全缓解 (CR) 率在 4-7% 范围内。 这些疗法的结果为免疫疗法治疗黑色素瘤的潜力提供了进一步的原理证明。 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，毒性较小的疫苗免疫疗法可以发挥作用，特别是在辅助治疗中。 FDA 批准的唯一用于切除高危黑色素瘤患者的辅助治疗是高剂量、全身性干扰素 α。 然而，干扰素α疗法的最新汇总分析强调，对于辅助治疗的患者来说，即使该疗法的生存优势也值得怀疑。 因此，迫切需要针对黑色素瘤的额外新疗法，既用于高风险切除黑色素瘤的辅助治疗，也用于治疗晚期疾病中不适合其他疗法或失败的患者。 人们普遍认为，改善疫苗治疗免疫结果的一种机制是优化 T 细胞向肿瘤部位的运输。 CXCR3 是 T 细胞上的趋化因子受体，通过遵循趋化因子梯度将 T 细胞引导至炎症部位。 已知 CXCR3 的配体（CXCL9 (MIG)、CXCL10 (IP-10) 和 CXCL11 (I-TAC)）由干扰素 γ (IFN-)13,14 诱导。 该方案建议施用肽疫苗来激活表达 CXCR3 的肿瘤抗原特异性 CD8+ T 细胞，然后使用瘤内干扰素 γ 来增加肿瘤部位的 CXCR3 配体 (CXCL9-11) 并招募 CXCR3+ T 细胞。 虽然接受疫苗与瘤内干扰素 γ（Actimmune，干扰素 γ-1b）联合治疗的参与者也有可能获得临床益处，但目前的研究无法测试临床结果。 拟议工作的主要目标是评估肽疫苗和瘤内干扰素γ组合的安全性，并评估肿瘤部位的免疫结果。