Tumor eradication by triplet therapy with BRAF inhibitor, TLR 7 agonist, and PD-1 antibody for BRAF-mutated melanoma

被引:3
作者
Nakamura, Kenta [1 ,2 ]
Yaguchi, Tomonori [1 ,3 ]
Murata, Masashi [4 ]
Ota, Yosuke [4 ]
Mikoshiba, Asuka [2 ]
Kiniwa, Yukiko [2 ]
Okuyama, Ryuhei [2 ]
Kawakami, Yutaka [1 ,5 ]
机构
[1] Keio Univ, Sch Med, Inst Adv Med Res, Div Cellular Signaling, Tokyo, Japan
[2] Shinshu Univ, Sch Med, Dept Dermatol, 3-1-1 Asahi, Matsumoto, Nagano 3908621, Japan
[3] Kyoto Univ, Grad Sch Med, Dept Immunol & Genom Med, Kyoto, Japan
[4] Sumitomo Pharm Co Ltd, Canc Res Unit, Osaka, Japan
[5] Int Univ Hlth & Welf, Sch Med, Dept Immunol, 4-3 Kozunomori, Narita, Chiba 2868686, Japan
关键词
BRAF; immune checkpoint inhibitors; melanoma; programmed death 1; Toll-like receptor 7; PLASMACYTOID DENDRITIC CELLS; METASTATIC MELANOMA; T-CELLS; SURVIVAL; CANCER; DABRAFENIB; IPILIMUMAB; NIVOLUMAB; RNA; EXPRESSION;
D O I
10.1111/cas.16251
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Programmed death 1 (PD-1)/programmed death-ligand 1 inhibitors are commonly used to treat various cancers, including melanoma. However, their efficacy as monotherapy is limited, and combination immunotherapies are being explored to improve outcomes. In this study, we investigated a combination immunotherapy involving an anti-PD-1 antibody that blocks the major adaptive immune-resistant mechanisms, a BRAF inhibitor that inhibits melanoma cell proliferation, and multiple primary immune-resistant mechanisms, such as cancer cell-derived immunosuppressive cytokines, and a Toll-like receptor 7 agonist that enhances innate immune responses that promote antitumor T-cell induction and functions. Using a xenogeneic nude mouse model implanted with human BRAF-mutated melanoma, a BRAF inhibitor vemurafenib was found to restore T-cell-stimulatory activity in conventional dendritic cells by reducing immunosuppressive cytokines, including interleukin 6, produced by human melanoma. Additionally, intravenous administration of the Toll-like receptor 7 agonist DSR6434 enhanced tumor growth inhibition by vemurafenib through stimulating the plasmacytoid dendritic cells/interferon-alpha/natural killer cell pathways and augmenting the T-cell-stimulatory activity of conventional dendritic cells. In a syngeneic mouse model implanted with murine BRAF-mutated melanoma, the vemurafenib and DSR6434 combination synergistically augmented the induction of melanoma antigen gp100-specific T cells and inhibited tumor growth. Notably, only triplet therapy with vemurafenib, DSR6434, and the anti-PD-1 antibody resulted in complete regression of SIY antigen-transduced BRAF-mutated melanoma in a CD8 T-cell-dependent manner. These findings indicate that a triple-combination strategy targeting adaptive and primary resistant mechanisms while enhancing innate immune responses that promote tumor-specific T cells may be crucial for effective tumor eradication.
引用
收藏
页码:2879 / 2892
页数:14
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