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Local therapy with combination TLR agonists stimulates systemic anti-tumor immunity and sensitizes tumors to immune checkpoint blockade.
Rwandamuriye, Francois Xavier; Wang, Tao; Zhang, Hanfu; Elaskalani, Omar; Kuster, Jorren; Ye, Xueting; Vitali, Breana; Schreurs, Juliët; Orozco Morales, M Lizeth; Norret, Marck; Evans, Cameron W; Zemek, Rachael M; Iyer, K Swaminathan; Lesterhuis, W Joost; Wylie, Ben.
Afiliación
  • Rwandamuriye FX; Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia.
  • Wang T; Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia.
  • Zhang H; School of Molecular Sciences, University of Western Australia, Crawley, WA, Australia.
  • Elaskalani O; Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia.
  • Kuster J; Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia.
  • Ye X; Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia.
  • Vitali B; Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia.
  • Schreurs J; Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia.
  • Orozco Morales ML; Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia.
  • Norret M; School of Molecular Sciences, University of Western Australia, Crawley, WA, Australia.
  • Evans CW; School of Molecular Sciences, University of Western Australia, Crawley, WA, Australia.
  • Zemek RM; Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia.
  • Iyer KS; School of Molecular Sciences, University of Western Australia, Crawley, WA, Australia.
  • Lesterhuis WJ; Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia.
  • Wylie B; Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia.
Oncoimmunology ; 13(1): 2395067, 2024.
Article en En | MEDLINE | ID: mdl-39188754
ABSTRACT
Toll-like receptor (TLR) agonists are being developed as anti-cancer therapeutics due to their potent immunostimulatory properties. However, clinical trials testing TLR agonists as monotherapy have often failed to demonstrate significant improvement over standard of care. We hypothesized that the anti-cancer efficacy of TLR agonist immunotherapy could be improved by combinatorial approaches. To prevent increased toxicity, often seen with systemic combination therapies, we developed a hydrogel to deliver TLR agonist combinations at low doses, locally, during cancer debulking surgery. Using tumor models of WEHI 164 and bilateral M3-9-M sarcoma and CT26 colon carcinoma, we assessed the efficacy of pairwise combinations of poly(IC), R848, and CpG in controlling local and distant tumor growth. We show that combination of the TLR3 agonist poly(IC) and TLR7/8 agonist R848 drives anti-tumor immunity against local and distant tumors. In addition, combination of local poly(IC) and R848 sensitized tumors to systemic immune checkpoint blockade, improving tumor control. Mechanistically, we demonstrate that local therapy with poly(IC) and R848 recruits inflammatory monocytes to the tumor draining lymph nodes early in the anti-tumor response. Finally, we provide proof of concept for intraoperative delivery of poly(IC) and R848 together via a surgically applicable biodegradable hydrogel.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Poli I-C / Inhibidores de Puntos de Control Inmunológico / Imidazoles Límite: Animals / Female / Humans Idioma: En Revista: Oncoimmunology Año: 2024 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Poli I-C / Inhibidores de Puntos de Control Inmunológico / Imidazoles Límite: Animals / Female / Humans Idioma: En Revista: Oncoimmunology Año: 2024 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos