Intratumoral delivery of TransCon™ TLR7/8 Agonist promotes sustained anti-tumor activity and local immune cell activation while minimizing systemic cytokine induction

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).

Applications and clinical trial landscape using Toll-like receptor agonists to reduce the toll of cancer

“…Intratumoral TransCon TLR7/8 Agonist is a prodrug of resiquimod 50,51 , a more potent derivative of the approved TLR7 agonist imiquimod 52 . To limit systemic effects, TransCon TLR7/8 Agonist was designed for intratumoral retention 50,51 .…”

“…Intratumoral TransCon TLR7/8 Agonist is a prodrug of resiquimod 50,51 , a more potent derivative of the approved TLR7 agonist imiquimod 52 . To limit systemic effects, TransCon TLR7/8 Agonist was designed for intratumoral retention 50,51 . It is currently being evaluated as monotherapy and in combination with pembrolizumab in a first-in-human phase 1/2 study (NCT04799054) of patients with advanced solid tumors.…”

Cancer Immunotherapy through Tissue Adhering Polymers

“…As the compound is introduced into the tumor, an immediate innate immune response is raised against the tumor tissues, likely through the release of inflammatory cytokines in the tumor microenvironment. [16][17][18] As the compound spreads throughout the tumor and the lymphatic system for an extended duration, a robust adaptive immune response is likely raised against the tumor. However, it is currently not possible to determine whether this response is driven solely by the unspecific sustained exposure to the TLR7/8a…”

“…15 Additionally, immunogenic polymeric conjugates or supramolecular assemblies can be injected intratumorally, or peritumorally, and potentiate anti-PD-1, IL-2, and potentially many other complementary immune therapies. [16][17][18][19] Intratumoral and peritumoral injection circumvents the pharmacokinetic challenges, by depositing a high concentration of the TLR 7/8 agonists, directly at the tumor, where it in turn will activate immune cells that are already exposed to tumor antigens. The limited exposure to immune cells systemically also decreases off-target side effects and toxicity.…”

Percutaneous Intratumoral Immunoadjuvant Gel Increases the Abscopal Effect of Cryoablation for Checkpoint Inhibitor Resistant Cancer

“…Following prior studies, the mechanism of action is expected to be due to dendritic cell recruitment from TLR 7 activation followed by T‐cell activation and cell mediated killing. [ 14,21,22 ]…”