Introduction:: Pleural mesothelioma is an aggressive type of cancer that forms in the outer lining of the lungs, heart, abdomen, and testes. Despite recent advances in oncology, improvements in treating mesothelioma has been limited, with 5-year survival rates remaining exceptionally low. Thus, there is an urgent need to develop novel treatments to address this aggressive form of cancer. As with other forms of cancer, mesothelioma results from an imbalance in host immune response, with the local tumor microenvironment exerting a suppressive effect on immune cells. Consequently, immunomodulating molecules represent an attractive and logical option to therapeutically treat mesothelioma. However, current attempts to modulate patients’ immune response have demonstrated limited efficacy and bolus dosing of systemic therapies often causes significant adverse effects. Furthermore, some immunomodulating therapies, like exogenous cytokines, have short half-lives and cannot be feasibly administered systemically. To address these challenges, we have developed encapsulated cells that constitutively express immunomodulatory agents which can be implanted for localized delivery of therapeutics.
Materials and Methods:: To develop compatible cell lines for delivery of immunomodulatory therapeutics, we modified ARPE-19 cells to express therapies using a PiggyBac transposase system. Therapeutic expression was confirmed and quantified using biomolecular assays to validate production levels. Engineered cells were then encapsulated in biocompatible hydrogel microcapsules to protect them from host immune response. The encapsulated cells were implanted in mice to validate productivity.
Results, Conclusions, and Discussions:: Therapeutic-expressing ARPE-19 cells lines were successfully developed to express multiple immunomodulatory therapeutics. Hydrogel microencapsulation protected cells from host immune response in mice. Initial studies of short-term delivery of encapsulated cells indicated that cells did not pose an increased safety risk for mice. We hypothesize that administering multiple therapeutics as combination regimens by co-delivering microcapsules containing different therapeutic-expressing cells may exert a synergistic effect on reducing tumor burden in vivo.
Our approach allows for local therapeutic delivery to treat mesothelioma by delivering hydrogel encapsulated cells that constitutively express immunomodulating therapies, with the potential for combination regimen administration. We hypothesize that such an approach will be more effective and tolerable in treating mesothelioma, improving patients’ prospects against an aggressive form of cancer.
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References (Optional): : 1. American Cancer Society. Survival Rates for Malignant Mesothelioma. Last revised March 2, 2023. Accessed April 29, 2023. https://www.cancer.org/cancer/malignant-mesothelioma/detection-diagnosis-staging/survival-statistics.html
