Dissertation
The use of resiquimod (RSQ) in treatment of melanoma
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2021
DOI: 10.17077/etd.005812
Abstract
Melanoma is responsible for most skin cancer-related deaths, despite accounting for only 1% of all skin cancer cases. At present, surgery is considered the most promising treatment as it can effectively cure stage 0 and stage I melanoma patients. However, there are cases where surgery cannot be implemented or ineffective. Various alternative treatments for melanoma are available and among them, immunotherapy emerges as the most promising. Nevertheless, immunotherapy efficacy can still be limited, especially when a single agent is used. Melanoma can have multiple cell death resistance mechanisms. Thus, combination treatments that target more than one mechanism at the same time can have more promising results as suggested by increasing evidence. Resiquimod (RSQ), an imidazoquinolinamine derivative and Toll-like receptor-7/8 (TLR-7/8) agonist, is a promising candidate for melanoma treatment, as indicated by both pre-clinical and clinical studies. In this dissertation, we explored two relatively new combinations for melanoma treatment based on RSQ: RSQ+anti-PD-1 (immune checkpoint blockade), and RSQ+silver nanoparticles (AgNP).The first part of the research explored the in vitro effects of RSQ and then the in vivo effect of the combination of RSQ and anti-PD-1 on the survival of melanoma-challenged mice. Anti-PD-1, an immune checkpoint inhibitor, works by preventing the interaction between PD-1 on immune cells (specifically activated T cells) and PDL-1 on melanoma cells, can be an effective melanoma treatment. However, the percentage of melanoma patients that benefit from anti-PD-1 monotherapy is low, and a hostile immunosuppressive tumor microenvironment (TME) may be at least partly responsible. RSQ could potentially enhance the antitumor activity of immune checkpoint blockade when these agents are combined as a treatment for melanoma. In this study, the effect of combining systemic anti-PD-1 and locally administered RSQ on the survival of melanoma-challenged mice was tested. Our results demonstrated that anti-PD-1 in combination with RSQ can significantly prolong the survival of melanoma-challenged mice, compared to untreated mice and mice treated with anti-PD-1 alone. In addition, the in vitro effect of RSQ on B16.F10 melanoma cells was also investigated. The results showed that RSQ had a direct anti-proliferative effect on melanoma cells and induced IL-12 production from melanoma cells. These direct effects of RSQ on melanoma cells may potentially explain the enhanced anti-melanoma effects of RSQ in vivo. Toxicity analysis was also performed based on the analysis of mice sera from treated mice. The results showed that all the treatments, including the RSQ+anti-PD-1 combination, appeared to be safe in mice. In conclusion, the combination of RSQ and anti-PD-1 may be a promising treatment for melanoma patients, especially as both treatments have independently already been used to treat melanoma patients.
The second part of the research investigated the in vitro effect of AgNP and the in vivo effect of RSQ and AgNP combination on the survival of melanoma-challenged mice. Over the last decade, the potential for AgNP to be used as an anti-melanoma agent has been supported by both in vitro and in vivo evidence. However, an undesirably high concentration of AgNP is often required to achieve an antitumor effect and therefore a combination treatment that can maintain or improve antitumor efficacy (with lower amounts of AgNP) while also reducing off-target effects is sought. In this study, the combination of AgNP and RSQ was investigated and shown to significantly prolong the survival of melanoma-challenged mice compared to untreated mice, while either agent alone did not. Toxicity analysis was also conducted and the results showed that all the treatments, RSQ+AgNP included, seemed to be safe in mice. Immune cell depletion studies could not implicate a statistically significant involvement of the adaptive immune response in the antitumor response observed from the AgNP+RSQ treatment. In conclusion, the combination of AgNP and RSQ is a new combination worthy of further investigation in the context of melanoma treatment.
In summary, the combinations of RSQ+anti-PD-1 and RSQ+AgNP exhibited higher anti-melanoma treatment efficacy than their monotherapy counterparts. Their toxicity profile also indicated their safety, at least in mice. Hence, both combinations emerge as potential candidates for melanoma treatment.
Details
- Title: Subtitle
- The use of resiquimod (RSQ) in treatment of melanoma
- Creators
- Supreeda Tambunlertchai
- Contributors
- Aliasger Salem (Advisor)Nicole Brogden (Committee Member)Lewis Stevens (Committee Member)Reza Nejadnik (Committee Member)Marie Gaine (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pharmacy
- Date degree season
- Summer 2021
- DOI
- 10.17077/etd.005812
- Publisher
- University of Iowa
- Number of pages
- xiv, 112 pages
- Copyright
- Copyright 2021 Supreeda Tambunlertchai
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 97-110).
- Public Abstract (ETD)
Melanoma continues to be the deadliest form of skin cancer despite the constant search for effective remedies and various available treatments. Increasing evidence showed that combination therapies possess better melanoma treatment efficacies. In this dissertation, we investigated two relatively new combinations for melanoma treatment: resiquimod (RSQ) and anti-PD-1, and RSQ and silver nanoparticles (AgNP). The studies involved synthesizing AgNP, testing the effect of AgNP and RSQ on melanoma cells, and testing the effect of the combinations mentioned on melanoma-implanted mice. The results showed that both RSQ and AgNP can directly inhibit melanoma cell growth in vitro. The animal studies also revealed that melanoma-implanted mice treated with both combinations (i.e. RSQ+anti-PD-1 and RSQ+AgNP) can survive longer than when the mice were treated with their monotherapy counterparts. The possible toxicity of the treatments was also assessed and the results demonstrated that all the treatments tested were safe in mice. In conclusion, RSQ+anti-PD-1, and RSQ+AgNP appeared to be promising candidates to be used in melanoma treatment.
- Academic Unit
- Pharmacy; Craniofacial Anomalies Research Center
- Record Identifier
- 9984124269102771
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