Reference Detail

Ref Type

Journal Article

PMID

(38894534)

Authors

Nakamura K, Yaguchi T, Murata M, Ota Y, Mikoshiba A, Kiniwa Y, Okuyama R, Kawakami Y

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer science			2024 Jun 18		Cancer Sci

URL

Abstract Text

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-α/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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
DSR6434	DSR6434	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
DSR6434		DSR-6434\|DSR 6434	TLR7 Agonist 12	DSR6434 is an agonist of TLR7, which induces IFNalpha production via stimulation of dendritic cells, potentially leading to increased cytotoxicity and antitumor immune response (PMID: 38894534).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	melanoma	sensitive	DSR6434 + unspecified PD-1 antibody + Vemurafenib	Preclinical	Actionable	In a preclinical study, treatment with the combination of Zelboraf (vemurafenib), DSR6434, and an anti-PD-1 antibody induced tumor regression and resulted in prolonged progression-free survival compared to either of the doublet combination therapies in a syngeneic mouse model of melanoma harboring BRAF V600E (PMID: 38894534).	38894534