Tumor vaccines with dsRNA adjuvant ARNAX induces antigen-specific tumor shrinkage without cytokinemia

Seya, Tsukasa; Takeda, Yohei; Matsumoto, Misako

doi:10.1080/2162402x.2015.1043506

Cited by 13 publications

(10 citation statements)

References 10 publications

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“…Lastly, the availability of clinical grade TLR3 ligand has long been an obstacle for the clinical translation of over a decade of encouraging pre-clinical data in mice. However, recent description of well-defined and homogeneous TLR3-specific ligands 58 , 59 has revived the interest for targeting TLR3 in patients. In conclusion, the results presented here further support the targeting of TLR3+ squamous lung cancers with TLR3 ligand alone or in combination with c-FLIP-inhibitory chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Release of c-FLIP brake selectively sensitizes human cancer cells to TLR3-mediated apoptosis

et al. 2018

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Toll-like receptor 3 (TLR3) mediates innate immune responses by sensing viral dsRNA, but also induces apoptosis selectively in cancer cells. Our analysis by immunohistochemistry revealed that TLR3 is frequently overexpressed in 130 non-small cell lung cancer (NSCLC) patients’ samples compared with normal bronchial epithelium (P < 0.0001, Mann–Whitney test), supporting the therapeutic potential of TLR3 ligand for this type of cancer. However, a proportion of TLR3-expressing cancer cell lines, including NSCLC, remain resistant to TLR3-mediated apoptosis, and the underlying mechanism of resistance remains unclear. We here investigated the molecular basis conferring resistance to non-transformed vs. transformed cells against TLR3-mediated cell death. In non-transformed epithelial cells cellular FLICE-like inhibitory protein (c-FLIP) and cellular Inhibitor of APoptosis (cIAPs) ubiquitin ligases exerted an efficient double brake on apoptosis signaling. In contrast, releasing only one of these two brakes was sufficient to overcome the resistance of 8/8 cancer cell lines tested. Remarkably, the release of the c-FLIP, but not cIAPs, brake only results in the sensitization of all human cancer cells to TLR3-mediated apoptosis. Taking advantage of the difference between transformed and non-transformed cells, we developed a rational strategy by combining the chemotherapeutic agent paclitaxel, which decreases c-FLIP expression, with TLR3 ligand. This combination was highly synergistic for triggering apoptosis in cancer cells but not in non-transformed cells. In vivo, the combination of paclitaxel with dsRNA delayed tumor growth and prolonged survival in a mouse xenograft lung tumor model. In conclusion, combining the release of the c-FLIP brake with TLR3 ligand synergizes to selectively kill cancer cells, and could represent an efficient and safe therapy against TLR3-expressing cancers such as NSCLC.

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Section: Discussionmentioning

confidence: 99%

Release of c-FLIP brake selectively sensitizes human cancer cells to TLR3-mediated apoptosis

et al. 2018

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“…Here, we explored the utility of combination therapy with anti-PD-L1 Ab and the non-inflammatory adjuvant, ARNAX, targeting endosomal Toll-like receptor 3 in DCs in a mouse tumor model (Matsumoto et al, 2015;Seya et al, 2015). Toll-like receptor 3 (TLR3) is highly expressed in professional Ag-presenting mouse CD8a + and CD103 + and human CD141 + DCs (Bachem et al, 2010;Jongbloed et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

A TLR3-Specific Adjuvant Relieves Innate Resistance to PD-L1 Blockade without Cytokine Toxicity in Tumor Vaccine Immunotherapy

et al. 2017

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Cancer patients having anti-programmed cell death-1 (PD-1)/PD ligand 1 (L1)-unresponsive tumors may benefit from advanced immunotherapy. Double-stranded RNA triggers dendritic cell (DC) maturation to cross-prime antigen-specific cytotoxic T lymphocytes (CTLs) via Toll-like receptor 3 (TLR3). The TLR3-specific RNA agonist, ARNAX, can induce anti-tumor CTLs without systemic cytokine/interferon (IFN) production. Here, we have developed a safe vaccine adjuvant for cancer that effectively implements anti-PD-L1 therapy. Co-administration of ARNAX with a tumor-associated antigen facilitated tumor regression in mouse models, and in combination with anti-PD-L1 antibody, activated tumor-specific CTLs in lymphoid tissues, enhanced CTL infiltration, and overcame anti-PD-1 resistance without cytokinemia. The TLR3-TICAM-1-interferon regulatory factor (IRF)3-IFN-β axis in DCs exclusively participated in CD8 T cell cross-priming. ARNAX therapy established Th1 immunity in the tumor microenvironment, upregulating genes involved in DC/T cell/natural killer (NK) cell recruitment and functionality. Human ex vivo studies disclosed that ARNAX+antigen induced antigen-specific CTL priming and proliferation in peripheral blood mononuclear cells (PBMCs), supporting the feasibility of ARNAX for potentiating anti-PD-1/PD-L1 therapy in human vaccine immunotherapy.

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“…This non-inflammatory TLR3 agonist was shown to synergize with PD-L1 blockade in tumor eradication in immunocompetent hosts to overcome PD-1/PD-L1 resistance and provide long-term protection from tumor relapse. The authors highlight the necessity of both proper DC priming by a TLR3 ligand and checkpoint inhibitor blockade for efficient cancer immunotherapy [38][39][40][41][42][43] .…”

Section: Discussionmentioning

confidence: 99%

PLGA-particle vaccine carrying TLR3/RIG-I ligand Riboxxim synergizes with immune checkpoint blockade for effective anti-cancer immunotherapy

et al. 2021

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With emerging supremacy, cancer immunotherapy has evolved as a promising therapeutic modality compared to conventional antitumor therapies. Cancer immunotherapy composed of biodegradable poly(lactic-co-glycolic acid) (PLGA) particles containing antigens and toll-like receptor ligands induces vigorous antitumor immune responses in vivo. Here, we demonstrate the supreme adjuvant effect of the recently developed and pharmaceutically defined double-stranded (ds)RNA adjuvant Riboxxim especially when incorporated into PLGA particles. Encapsulation of Riboxxim together with antigens potently activates murine and human dendritic cells, and elevated tumor-specific CD8+ T cell responses are superior to those obtained using classical dsRNA analogues. This PLGA particle vaccine affords primary tumor growth retardation, prevention of metastases, and prolonged survival in preclinical tumor models. Its advantageous therapeutic potency was further enhanced by immune checkpoint blockade that resulted in reinvigoration of cytotoxic T lymphocyte responses and tumor ablation. Thus, combining immune checkpoint blockade with immunotherapy based on Riboxxim-bearing PLGA particles strongly increases its efficacy.

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Tumor vaccines with dsRNA adjuvant ARNAX induces antigen-specific tumor shrinkage without cytokinemia

Cited by 13 publications

References 10 publications

Release of c-FLIP brake selectively sensitizes human cancer cells to TLR3-mediated apoptosis

Release of c-FLIP brake selectively sensitizes human cancer cells to TLR3-mediated apoptosis

A TLR3-Specific Adjuvant Relieves Innate Resistance to PD-L1 Blockade without Cytokine Toxicity in Tumor Vaccine Immunotherapy

PLGA-particle vaccine carrying TLR3/RIG-I ligand Riboxxim synergizes with immune checkpoint blockade for effective anti-cancer immunotherapy

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