| Autor: |
Luis Alejandro Zúñiga, Torben Leßmann, Karan Uppal, Nicola Bisek, Enping Hong, Caroline E. Rasmussen, Jens-Jakob Karlsson, Joachim Zettler, Lars Holten-Andersen, Kathy Bang, Dhruv Thakar, Yu-Chi Lee, Salomon Martinez, Simran Singh Sabharwal, Sebastian Stark, Frank Faltinger, Oliver Kracker, Samuel Weisbrod, Robin Müller, Tobias Voigt, Kornelia Bigott, Mohammad Tabrizifard, Vibeke Miller Breinholt, Amer M. Mirza, David B. Rosen, Kennett Sprogøe, Juha Punnonen |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Cancer Cell International, Vol 22, Iss 1, Pp 1-17 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
1475-2867 |
| DOI: |
10.1186/s12935-022-02708-6 |
| Popis: |
Abstract Background Intratumoral (IT) delivery of toll-like receptor (TLR) agonists has shown encouraging anti-tumor benefit in preclinical and early clinical studies. However, IT delivery of TLR agonists may lead to rapid effusion from the tumor microenvironment (TME), potentially limiting the duration of local inflammation and increasing the risk of systemic adverse events. Methods To address these limitations, TransCon™ TLR7/8 Agonist—an investigational sustained-release prodrug of resiquimod that uses a TransCon linker and hydrogel technology to achieve sustained and predictable IT release of resiquimod—was developed. TransCon TLR7/8 Agonist was characterized for resiquimod release in vitro and in vivo, in mice and rats, and was assessed for anti-tumor efficacy and pharmacodynamic activity in mice. Results Following a single IT dose, TransCon TLR7/8 Agonist mediated potent tumor growth inhibition which was associated with sustained resiquimod release over several weeks with minimal induction of systemic cytokines. TransCon TLR7/8 Agonist monotherapy promoted activation of antigen-presenting cells in the TME and tumor-draining lymph nodes, with evidence of activation and expansion of CD8+ T cells in the tumor-draining lymph node and TME. Combination of TransCon TLR7/8 Agonist with systemic immunotherapy further promoted anti-tumor activity in TransCon TLR7/8 Agonist-treated tumors. In a bilateral tumor setting, combination of TransCon TLR7/8 Agonist with systemic IL-2 potentiated tumor growth inhibition in both injected and non-injected tumors and conferred protection against tumor rechallenge following complete regressions. Conclusions Our findings show that a single dose of TransCon TLR7/8 Agonist can mediate sustained local release of resiquimod in the TME and promote potent anti-tumor effects as monotherapy and in combination with systemic immunotherapy, supporting TransCon TLR7/8 Agonist as a novel intratumoral TLR agonist for cancer therapy. A clinical trial to evaluate the safety and efficacy of TransCon TLR7/8 Agonist, as monotherapy and in combination with pembrolizumab, in cancer patients is currently ongoing (transcendIT-101; NCT04799054). |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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