Employing Drug Delivery Strategies to Overcome Challenges Using TLR7/8 Agonists for Cancer Immunotherapy

Abstract

Toll-like receptors (TLRs) are a potential target for cancer immunotherapy due to their role in the activation of the innate immune system. More specifically, TLR7/8, two structurally similar pattern recognition receptors that trigger interferon and cytokine responses, have proven to be therapeutically relevant targets for cancer in numerous preclinical and clinical studies. When triggered by an agonist, such as imiquimod or resiquimod, the TLR7/8 activation pathway induces cellular and humoral immune responses that can kill cancer cells with high specificity. Unfortunately, TLR7/8 agonists also present a number of issues that must be overcome prior to broad clinical implementation, such as poor drug solubility and systemic toxic effects. To overcome the key limitations of TLR7/8 agonists as a cancer therapy, biomaterial-based drug delivery systems have been developed. These delivery devices are highly diverse in their design and include systems that can be directly administered to the tumor, passively accumulated in relevant cancerous and lymph tissues, triggered by environmental stimuli, or actively targeted to specific physiological areas and cellular populations. In addition to improved delivery systems, recent studies have also demonstrated the potential benefits of TLR7/8 agonist codelivery with other types of therapies, particularly checkpoint inhibitors, cancer vaccines, and chemotherapeutics, which can yield impressive anti-cancer effects. In this review, we discuss recent advances in the development of TLR7/8 agonist delivery systems and provide perspective on promising future directions.

Engineered red blood cells (activating antigen carriers) drive potent T cell responses and tumor regression in mice

“…However, for the carriers to induce antigen-specific immune activation and not tolerance, the addition of both antigen and adjuvant is required ( 35 – 38 ). TLR agonists are used as vaccine adjuvants in anti-cancer therapies because of their ability to activate immune cells and promote inflammation ( 14 , 39 – 43 ). To demonstrate that our carriers can activate endogenous T cells as a consequence of the encapsulated antigen and adjuvant, RBCs were processed with the model antigen ovalbumin and poly I:C, a TLR3 agonist, which has been shown to promote cross-presentation by DCs as well as upregulate co-stimulatory and cytokine signals ( 44 – 47 ).…”

Novel Vaccine Adjuvants as Key Tools for Improving Pandemic Preparedness

“…When stimulated with imiquimod or similar small molecule agonists, TLR7/8 induces both humoral and cellular immunity. Unfortunately, these molecules also exhibit poor water solubility and high toxicity [ 69 ]. However, formulation with delivery vehicles such as liposomes, nanoparticles, or nanofibers can enhance the safety, solubility, and immunogenicity of these adjuvants [ 70 , 71 , 72 ].…”

Role of Toll-Like Receptors in Neuroimmune Diseases: Therapeutic Targets and Problems

“…Although many TLR inhibitors have been developed, they have not been used for clinical treatments mainly due to its inadequate response (206), especially with traditional delivery methods: insufficient stability, poor water solubility, injection site aggregation, not lasting effect, systemic toxicity, and nonspecific immune cell suppression (207)(208)(209). Developing accurate targeted drugs and effective delivery method are the most important issue.…”