Anti-programmed death (PD)-1 (aPD1) therapy is an effective treatment for metastatic melanoma (MM); however, over 50% of patients progress due to resistance. We tested a first-in-class immune-modulatory vaccine (IO102/IO103) against indoleamine 2,3-dioxygenase (IDO) and PD ligand 1 (PD-L1), targeting immunosuppressive cells and tumor cells expressing IDO and/or PD-L1 (IDO/PD-L1), combined with nivolumab. Thirty aPD1 therapy-naive patients with MM were treated in a phase 1/2 study (https://clinicaltrials.gov/, NCT03047928). The primary endpoint was feasibility and safety; the systemic toxicity profile was comparable to that of nivolumab monotherapy. Secondary endpoints were efficacy and immunogenicity; an objective response rate (ORR) of 80% (confidence interval (CI), 62.7–90.5%) was reached, with 43% (CI, 27.4–60.8%) complete responses. After a median follow-up of 22.9 months, the median progression-free survival (PFS) was 26 months (CI, 15.4–69 months). Median overall survival (OS) was not reached. Vaccine-specific responses assessed in vitro were detected in the blood of >93% of patients during vaccination. Vaccine-reactive T cells comprised CD4⁺ and CD8⁺ T cells with activity against IDO- and PD-L1-expressing cancer and immune cells. T cell influx of peripherally expanded T cells into tumor sites was observed in responding patients, and general enrichment of IDO- and PD-L1-specific clones after treatment was documented. These clinical efficacy and favorable safety data support further validation in a larger randomized trial to confirm the clinical potential of this immunomodulating approach.

抗程序性死亡（PD）-1（aPD1）疗法是治疗转移性黑色素瘤（MM）的有效方法；然而，超过 50% 的患者由于耐药性而进展。我们测试了针对吲哚胺 2,3-双加氧酶 (IDO) 和 PD 配体 1 (PD-L1) 的一流免疫调节疫苗 (IO102/IO103)，靶向表达 IDO 和/或 PD-的免疫抑制细胞和肿瘤细胞L1 (IDO/PD-L1)，联合纳武单抗。在 1/2 期研究（https://clinicaltrials.gov/，NCT03047928）中治疗了 30 名 aPD1 初治 MM 患者。主要终点是可行性和安全性；全身毒性特征与 nivolumab 单药疗法相当。次要终点是疗效和免疫原性；客观缓解率 (ORR) 达到 80%（置信区间 (CI)，62.7–90.5%），其中 43%（CI，27.4–60.8%）完全缓解。中位随访 22.9 个月后，中位无进展生存期 (PFS) 为 26 个月 (CI，15.4–69 个月)。未达到中位总生存期 (OS)。在疫苗接种期间，>93% 的患者血液中检测到体外评估的疫苗特异性反应。疫苗反应性 T 细胞包含 CD4⁺和 CD8 ⁺ T 细胞，对表达 IDO 和 PD-L1 的癌细胞和免疫细胞具有活性。在有反应的患者中观察到外周扩增的 T 细胞流入肿瘤部位，并记录了治疗后 IDO 和 PD-L1 特异性克隆的普遍富集。这些临床疗效和有利的安全性数据支持在更大规模的随机试验中进一步验证，以确认这种免疫调节方法的临床潜力。