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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 黑色素瘤疫苗与3-6%的晚期可测量疾病患者的主要消退相关。 这提供了黑色素瘤疫苗临床益处潜力的原理证明。 然而，一些黑色素瘤疫苗在几个III期临床试验中获得了阴性结果。 另一方面，至少有两项试验的亚组分析表明，参与者亚组可能获益。 使用多肽疫苗的UVA经验包括在大多数受试者中诱导抗肿瘤免疫，在辅助治疗环境中接受治疗的受试者的临床结局超过预测结局，以及在晚期转移性疾病环境中接受疫苗治疗的受试者中5-10%的临床肿瘤消退。 几种其他免疫疗法，包括高剂量白细胞介素-2（FDA批准用于晚期黑色素瘤）、抗CTLA 4抗体和过继性T细胞疗法，已诱导黑色素瘤的显著消退，报告的客观缓解率分别为17%、13%和51%，完全缓解（CR）率在4- 7%的范围内。 这些疗法的结果为免疫疗法在黑色素瘤中的治疗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限制了参与者的资格;因此，毒性较小的疫苗免疫疗法具有一定的作用，特别是在辅助治疗中。 唯一FDA批准的用于切除高危黑色素瘤患者的辅助治疗是大剂量全身性干扰素α。 然而，最新的干扰素α治疗的汇总分析强调了即使是这种治疗在辅助治疗中的患者的生存优势也是值得怀疑的。 因此，迫切需要用于黑素瘤的额外新疗法，用于高风险切除的黑素瘤的辅助疗法和用于在晚期疾病背景下不是其它疗法的候选者或其它疗法失败的患者的疗法。 人们普遍认为，改善疫苗治疗的免疫结果的一种机制是优化T细胞向肿瘤部位的运输。 CXCR 3是T细胞上的趋化因子受体，其通过遵循趋化因子梯度将它们引导至炎症部位。 已知CXCR 3的配体（CXCL 9（IFN-γ）、CXCL 10（IP-10）和CXCL 11（I-TAC））由干扰素γ（IFN-γ）诱导13，14。 该方案提出施用肽疫苗以激活表达CXCR 3的肿瘤抗原特异性CD 8 + T细胞，然后瘤内干扰素γ以增加肿瘤部位的CXCR 3配体（CXCL 9 -11）并募集CXCR 3 + T细胞。 虽然接受疫苗联合瘤内干扰素γ（Actimune，干扰素γ-1b）的参与者也有可能获得临床益处，但目前的研究没有能力测试临床结果。 这项工作的主要目的是评估肽疫苗和瘤内干扰素γ联合治疗的安全性，并评估肿瘤部位的免疫学结果。