INTRATUMORAL INTERFERON GAMMA DURING VACCINATION IN METASTATIC MELANOMA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 黑色素瘤疫苗与3-6%的晚期可测量疾病患者的重大退化有关。这为黑色素瘤疫苗的临床益处提供了原则证明。然而，在一些黑色素瘤疫苗的几个第三阶段临床试验中，已经获得了阴性结果。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，在佐剂环境下接受治疗的参与者的临床结果超出预期结果，以及在晚期转移疾病环境下接受疫苗治疗的5%-10%的参与者的临床肿瘤消退。其他几种免疫疗法，包括大剂量白介素2(FDA批准用于晚期黑色素瘤)、抗CTLA4抗体和过继T细胞疗法，也可以诱导黑色素瘤显著消退，报道的客观应答率分别为17%、13%和51%，完全应答率(CR)在4-7%之间。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，毒性较低的疫苗免疫疗法具有一定的作用，特别是在佐剂环境中。FDA批准的用于切除的高危黑色素瘤患者的唯一辅助疗法是大剂量、系统性干扰素α。然而，最近对干扰素α疗法的综合分析强调了即使是这种疗法对处于辅助环境中的患者来说也有可疑的生存优势。因此，迫切需要额外的黑色素瘤新疗法，既用于高危切除黑色素瘤的辅助治疗，也用于治疗不适合或失败于晚期疾病的其他疗法的患者。 人们普遍认为，改善疫苗治疗的免疫学结果的一个机制是优化T细胞向肿瘤部位的运输。CXCR3是T细胞上的趋化因子受体，通过跟随趋化因子梯度将T细胞导向炎症部位。CXCR3的配体(CXCL9(MIG)、CXCL10(IP-10)和CXCL11(I-TAC))是已知由干扰素-13、14诱导的。该方案建议使用肽疫苗来激活表达CXCR3的肿瘤抗原特异性CD8+T细胞，然后瘤内注射干扰素以增加肿瘤部位的CXCR3配体(CXCL9-11)并招募CXCR3+T细胞。 虽然接受疫苗和肿瘤内干扰素伽马(Actimmune，干扰素-1b)联合接种的参与者也有可能获得临床益处，但这项当前的研究并不能测试临床结果。拟议工作的主要目标是评估多肽疫苗和肿瘤内干扰素伽马的组合的安全性，并评估肿瘤部位的免疫学结果。

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.