Immunostimulatory TLR7 Agonist‐Nanoparticles Together with Checkpoint Blockade for Effective Cancer Immunotherapy

Abstract

Mono‐ or dual‐checkpoint inhibitors for immunotherapy have changed the paradigm of cancer care; however, only a minority of patients responds to such treatment. Combining small molecule immunostimulators can improve treatment efficacy, but they are restricted by poor pharmacokinetics. In this study, conjugated TLR7 agonists onto silica nanoparticles show extended drug localization after intratumoral injection. The nanoparticle‐based TLR7 agonist increases immune stimulation by activating the TLR7 signaling pathway. When treating CT26 colon cancer, nanoparticle conjugated TLR7 agonists increase T cell infiltration into the tumors by >4× and upregulate expression of the interferon γ gene compared to its unconjugated counterpart by ≈2×. Toxicity assays establish that the conjugated TLR7 agonist is a safe agent at the effective dose. When combined with checkpoint inhibitors that target programmed cell death protein 1 (PD‐1) and cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4), a 10–100× increase in immune cell migration is observed; furthermore, 100 mm3 tumors are treated, and a 60% remission rate is observed including remission at contralateral noninjected tumors. The data show that nanoparticle‐based TLR7 agonists are safe and can potentiate the effectiveness of checkpoint inhibitors in immunotherapy resistant tumor models and promote a long‐term specific memory immune function.

A Redox‐Responsive Nanovaccine Combined with A2A Receptor Antagonist for Cancer Immunotherapy

“…The 4T1 tumor model was in situ established in specific pathogen‐free female Balb/c mice, and the treatment schedule is shown in Figure . According to different treatment methods, the mice bearing 4T1 tumors were divided into eight groups: 1) Saline, 2) SCH58261 (a dosage of 1 mg kg −1 ), [ 18 ] 3) Anti‐CTLA4 (a dosage of 5 mg kg −1 ), [ 24 ] 4) DOX + R848 (a dosage of DOX 5 mg kg −1 , [ 25 ] a dosage of R848 2.5 mg kg −1 ), 5) D/R@RPsP (a dosage of DOX 5 mg kg −1 ), 6) DOX + R848 + SCH58261 (a dosage of DOX 5 mg kg −1 , a dosage of R848 2.5 mg kg −1 , a dosage of SCH58261 1 mg kg −1 ), 7) D/R@mPsP + SCH58261(a dosage of DOX 5 mg kg −1 , a dosage of SCH58261 1 mg kg −1 ), and 8) D/R@RPsP + SCH58261(a dosage of DOX 5 mg kg −1 , a dosage of SCH58261 1 mg kg −1 ). All drug components were injected intravenously, with the removal of SCH58261 and Anti‐CTLA4 by intraperitoneal injection.…”

“…All drug components were injected intravenously, with the removal of SCH58261 and Anti‐CTLA4 by intraperitoneal injection. [ 18,24,26 ] It could be observed from Figure S12, Supporting Information, and Figure 3b that the tumor size in group (1) had increased significantly and other groups were increased in varying degrees. Among the eight groups, the tumors of two mice in group (8) had disappeared completely (Figure 3c,d).…”

WGCNA identification of TLR7 as a novel diagnostic biomarker, progression and prognostic indicator, and immunotherapeutic target for stomach adenocarcinoma

“…Further, when combined with PDCD1 and CTLA4 inhibitors, the infiltration of immune cells is more significantly increased. 33 Mariola et al suggested that TLR7 has the potential to induce CD4+T cells and CD8+T cell infiltration into the tumor microenvironment. 34 Overall, previous studies have shown that TLR7 indeed promotes immune cell infiltration, and TLR7 combined with ICB could markedly improve the clinical outcomes of many patients with cancer.…”

Evolution of Toll-like receptor 7/8 agonist therapeutics and their delivery approaches: From antiviral formulations to vaccine adjuvants

“…Although TLR7/8 agonists could be substituted by TLR9 agonists, surprisingly, checkpoint inhibitors against PD-1, PD-L1, or CTLA-4 could not substitute for anti-OX40 antibodies. A number of other studies, however, have reported synergy between TLR7/8 agonists and checkpoint inhibitors in various other murine tumor models [ 336 - 339 ]. Other attempts to augment the efficacy of synthetic TLR7/8 agonists have included combinations with antibodies such as anti-EGFR and anti-HER2/neu, cytokines such as IL-2, and photothermal therapies [ 340 - 345 ].…”