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Immunostimulatory TLR7 Agonist‐Nanoparticles Together with Checkpoint Blockade for Effective Cancer Immunotherapy
Author(s) -
Huang ChingHsin,
Mendez Natalie,
Echeagaray Oscar Hernandez,
Weeks Joi,
Wang James,
Yao Shiyin,
Blair Sarah L.,
Gude Natalie,
Trogler William C.,
Carson Dennis A.,
Hayashi Tomoko,
Kummel Andrew C.
Publication year - 2020
Publication title -
advanced therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
0ISSN - 2366-3987
DOI - 10.1002/adtp.201900200
Subject(s) - tlr7 , agonist , immunotherapy , cancer immunotherapy , cancer research , pharmacology , abscopal effect , immune checkpoint , t cell , immune system , medicine , receptor , immunology , innate immune system , toll like receptor
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 mm 3 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.