Malignant Pleural Mesothelioma (MPM) is a highly aggressive pleural malignancy that is lethal in essentially all cases. Few effective treatments exist and 5-year mortality is >90%. Cytokine therapy has tremendous potential for cancer patients, but serious technological limitations remain. The inherent instability of recombinant cytokines is one of the key obstacles to clinical application. The instability necessitates high/frequent doses which also cause severe toxicities and patients are often forced to stop treatments. New drug delivery platforms which provide spatial and temporal control over delivery of immunotherapy payloads can significantly improve therapy outcomes while reducing t...

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Malignant Pleural Mesothelioma (MPM) is a highly aggressive pleural malignancy that is lethal in essentially all cases. Few effective treatments exist and 5-year mortality is >90%. Cytokine therapy has tremendous potential for cancer patients, but serious technological limitations remain. The inherent instability of recombinant cytokines is one of the key obstacles to clinical application. The instability necessitates high/frequent doses which also cause severe toxicities and patients are often forced to stop treatments. New drug delivery platforms which provide spatial and temporal control over delivery of immunotherapy payloads can significantly improve therapy outcomes while reducing toxicities. To address this challenge, here we propose development of a programmable drug delivery platform that consists of immunomodulatory hydrogels encapsulating engineered cells that produce proinflammatory cytokines. This system allows for continuous local (tumor adjacent) delivery of high concentrations of natural cytokines while limiting systemic exposure to address limitations in cytokine persistence as well as toxicities seen with systemic administration. To develop this platform, we leverage small molecule modified alginate analogs that can interface with host immune cells to control the duration of capsule persistence in vivo, allowing for programed durability of treatment regimens. A major benefit of our cell produced cytokines is that they are more potent and bioactive than their recombinant counterparts. Putative lead platform formulations tested in mouse models of cancer show ability to produce durable cure in intractable mouse models. To ensure safety for clinical translation, we propose to incorporate small molecule inducible kill switches that would allow clinicians to safely terminate therapy on demand.

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