Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.
Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, Universidad de Chile, Santiago, Chile.
J Immunother Cancer. 2020 Jul;8(2). doi: 10.1136/jitc-2020-000999.
Immune checkpoint blocker (ICB) therapy has shown survival benefits for some patients with cancer. Nevertheless, many individuals remain refractory or acquire resistance to treatment, motivating the exploration of complementary immunotherapies. Accordingly, cancer vaccines offer an attractive alternative. Optimal delivery of multiple tumor-associated antigens combined with potent adjuvants seems to be crucial for vaccine effectiveness.
Here, a prototype for a generic melanoma vaccine, named TRIMELVax, was tested using B16F10 mouse melanoma model. This vaccine is made of heat shock-treated tumor cell lysates combined with the hemocyanin as adjuvant.
While B16F10 lysate provides appropriate melanoma-associated antigens, both a generic human melanoma cell lysate and hemocyanin adjuvant contributes with danger signals promoting conventional dendritic type 1 cells (cDC1), activation, phagocytosis and effective antigen cross-presentation. TRIMELVax inhibited tumor growth and increased mice survival, inducing cellular and humoral immune responses. Furthermore, this vaccine generated an increased frequency of intratumor cDC1s but not conventional type 2 dendritic cells (cDC2s). Augmented infiltration of CD3, CD4 and CD8 T cells was also observed, compared with anti-programmed cell death protein 1 (PD-1) monotherapy, while TRIMELVax/anti-PD-1 combination generated higher tumor infiltration of CD4 T cells. Moreover, TRIMELVax promoted an augmented proportion of PD-1 CD8 T cells in tumors, a phenotype associated with prototypic effector cells required for tumor growth control, preventing dysfunctional T-cell accumulation.
The therapeutic vaccine TRIMELVax efficiently controls the weakly immunogenic and aggressive B16F10 melanoma tumor growth, prolonging tumor-bearing mice survival even in the absence of ICB. The strong immunogenicity shown by TRIMELVax encourages clinical studies in patients with melanoma.
免疫检查点阻断（ICB）疗法已显示出对某些癌症患者的生存益处。然而，许多人仍然对治疗产生耐药性或产生耐药性，这促使人们探索互补的免疫疗法。相应地，癌症疫苗提供了一种有吸引力的选择。最佳地递呈多种肿瘤相关抗原并结合有效的佐剂对于疫苗的有效性似乎至关重要。
在这里，使用 B16F10 小鼠黑色素瘤模型测试了一种名为 TRIMELVax 的通用黑色素瘤疫苗的原型。该疫苗由热休克处理的肿瘤细胞裂解物与血蓝蛋白佐剂组成。
虽然 B16F10 裂解物提供了适当的黑色素瘤相关抗原，但通用的人类黑色素瘤细胞裂解物和血蓝蛋白佐剂都提供了促进常规树突状细胞 1 型（cDC1）、激活、吞噬和有效抗原交叉呈递的危险信号。TRIMELVax 抑制肿瘤生长并增加小鼠存活率，诱导细胞和体液免疫反应。此外，与抗程序性细胞死亡蛋白 1（PD-1）单药治疗相比，该疫苗在肿瘤内产生了更多的 cDC1，但没有常规的 2 型树突状细胞（cDC2）。与抗 PD-1 单药治疗相比，还观察到 CD3、CD4 和 CD8 T 细胞的浸润增加，而 TRIMELVax/抗 PD-1 联合治疗则导致肿瘤内 CD4 T 细胞浸润增加。此外，TRIMELVax 促进了肿瘤中 PD-1 CD8 T 细胞比例的增加，这种表型与控制肿瘤生长所需的典型效应细胞相关，防止了功能失调的 T 细胞积累。
治疗性疫苗 TRIMELVax 有效地控制了弱免疫原性和侵袭性的 B16F10 黑色素瘤肿瘤生长，延长了荷瘤小鼠的存活时间，即使在没有 ICB 的情况下也是如此。TRIMELVax 表现出的强免疫原性鼓励对黑色素瘤患者进行临床研究。
