An injectable superior depot of Telratolimod inhibits post-surgical tumor recurrence and distant metastases

by Selleckchem | Sep 17 2023

The clinical success of Toll-like receptor (TLR) agonists is based on their capacity to efficiently mobilize both innate and adaptive immunity. However, rapid distribution of TLR agonists into the systemic circulation may result in systemic cytokine storms. Telratolimod (Tel) is a TLR 7/8 agonist whose structure has a hydrophobic long chain that helps to prolong its release. Despite this, the phase I study of Tel showed cytokine release syndromes in 3/35 patients. Herein, we designed an injectable phase transition gel (PGE) that served as a superior drug depot for fatty acid-modified drugs. PGE further minimized the systemic drug exposure of Tel and the possible cytokine storms. In vivo studies demonstrated that Tel@PGE facilitated the recruitment of effector CD8+ T lymphocytes (T cells) and the polarization of myeloid-derived suppressor cells (MDSCs) and immunosuppressive M2-like macrophages to tumoricidal antigen-presenting cells. The reshaping of the tumor microenvironment (TME) by Tel@PGE elicited systematic immune responses to significantly prevent B16F10 or 4T-1 tumor postoperative recurrence and metastasis. Therefore, this platform of Tel is expected to provide a clinically available option for effective postoperative combined therapy. STATEMENT OF SIGNIFICANCE: A series of prodrugs or conjugates containing hydrophobic blocks were designed to achieve sustained release at the injection site by reducing the water solubility. However, this strategy sometimes failed short of expectations. Thus, we constructed a biocompatible and biodegradable injectable phase transition gel (PGE) with superior release properties that can be injected subcutaneously into the surgery site. In the long-lasting treatment, the melanoma and breast cancer immunotherapeutic effect significantly enhanced and the risk of cancer metastasis and relapse was reduced. Crucially, for some immune agonists, a superior release control can significantly reduce adverse effects which was decisive for the availability of the drugs.

Comments:

The passage you provided describes the development and potential benefits of an injectable phase transition gel (PGE) for the delivery of the Toll-like receptor (TLR) agonist telratolimod (Tel). TLR agonists are known for their ability to activate both innate and adaptive immunity. However, the systemic distribution of TLR agonists can lead to excessive cytokine release, known as cytokine storms, which can cause adverse effects.

Telratolimod (Tel) is a TLR 7/8 agonist that has a hydrophobic long chain structure, which helps to prolong its release. Despite this design, the phase I study of Tel showed cytokine release syndromes in a subset of patients. To address this issue, the researchers designed an injectable phase transition gel (PGE) that could serve as a drug depot for fatty acid-modified drugs like Tel. This gel formulation aimed to minimize systemic drug exposure and reduce the risk of cytokine storms.

In in vivo studies, Tel@PGE (Tel incorporated into the PGE) demonstrated several positive effects on the immune system. It facilitated the recruitment of effector CD8+ T lymphocytes (T cells), as well as the polarization of myeloid-derived suppressor cells (MDSCs) and immunosuppressive M2-like macrophages into tumoricidal antigen-presenting cells. This reshaping of the tumor microenvironment (TME) by Tel@PGE elicited systematic immune responses that significantly reduced the recurrence and metastasis of B16F10 or 4T-1 tumors after surgery.

The significance of this study lies in the development of the injectable phase transition gel (PGE) as a drug delivery platform for hydrophobic immune agonists like Tel. This gel provides superior release properties and can be injected subcutaneously at the surgery site. By achieving sustained release and reducing systemic exposure, PGE offers a way to enhance the therapeutic effects of immunotherapy while reducing the risk of adverse effects. The controlled release of immune agonists can be crucial for improving their clinical availability and safety.