Generating responses to tumor antigens poses a challenge for immunotherapy. This phase II trial (NCT02129075) tested fms-like tyrosine kinase 3 (Flt3) ligand pre-treatment enhancement of responses to dendritic cell (DC)-targeting vaccines. We evaluated a regimen of Flt3L (CDX-301) to increase DCs and other antigen-presenting cells, poly-ICLC (TLR3 agonist that activates DCs) and a vaccine comprising anti-DEC-205-NY-ESO-1, a fusion antibody targeting CD205, linked to NY-ESO-1. High-risk melanoma patients were randomized to vaccine, with and without CDX-301. The end point was immune response to NY-ESO-1. Flt3L increased peripheral monocytes and conventional DCs (cDCs), including cross-presenting cDC1 and cDC2 and plasmacytoid DCs. Significant increases in humoral and T-cell responses and activation of DCs, natural killer cells and T cells were elicited. Transcriptional analyses revealed gene signatures associated with CDX-301 induction of an early, durable immune response. This study reveals in vivo effects of Flt3L on innate immune cells in the setting of vaccination, leading to an immunogenic vaccine regimen.

产生对肿瘤抗原的反应对免疫治疗提出了挑战。该 II 期试验 (NCT02129075) 测试了 fms 样酪氨酸激酶 3 (Flt3) 配体预处理增强对树突状细胞 (DC) 靶向疫苗的反应。我们评估了 Flt3L (CDX-301) 方案以增加 DCs 和其他抗原呈递细胞、poly-ICLC（激活 DCs 的 TLR3 激动剂）和包含抗-DEC-205-NY-ESO-1（一种融合抗体）的疫苗针对 CD205，链接到 NY-ESO-1。高危黑色素瘤患者随机接种疫苗，有和没有 CDX-301。终点是对 NY-ESO-1 的免疫反应。Flt3L 增加外周单核细胞和常规 DCs (cDCs)，包括交叉呈递 cDC1 和 cDC2 以及浆细胞样 DCs。体液和 T 细胞反应和 DC 激活显着增加，引出自然杀伤细胞和T细胞。转录分析揭示了与 CDX-301 诱导早期持久免疫反应相关的基因特征。该研究揭示了 Flt3L 在疫苗接种环境中对先天免疫细胞的体内影响，从而产生了免疫原性疫苗方案。