Interleukin-7-producing Genetically Engineered Macrophages as a Tool to Enhance the Efficacy of CAR T Cells in Solid Tumors
Kole DeGolier*, Nicole Lieberman, Adam Johnson, Katherine Brempelis, Michael Jensen & Courtney Crane
Seattle Children’s Research Institute, Seattle, WA 98101, USA
Despite their success against hematologic malignancies, treatment of solid tumors using chimeric antigen receptor (CAR) T cells has been met with many challenges, including an immunosuppressive tumor microenvironment (TME) that decreases the survival and proliferation of T cells. Attempts to improve the function of endogenous or exogenous T cells via systemic delivery of immune enhancing agents have been associated with side effects such as the onset of auto-immune reactions. For example, IL-2 is known to increase the survival and proliferation of T cells, but is highly toxic and can impact multiple organ systems when administered systemically. IL-2 can also stimulate regulatory T cells (Tregs), which hinder an anti-tumor immune response. Our lab has designed a novel way to locally deliver an IL-2 signal to CAR T cells, while avoiding off-target effects on Tregs or toxicity to other tissues. In our model, we have used lentiviral vectors to create genetically engineered macrophages (GEMs) that secrete IL-7, signaling CAR T cells that express a chimeric cytokine receptor (ChCR) that pairs an extracellular IL-7 receptor with an intracellular IL-2 signal response. We have shown that IL-7-secreting GEMs are able to produce physiologically significant amounts of IL-7 and induce proliferation of CAR T cells in vitro. Additionally, adoptively transferred GEMs can persist in the tumor microenvironment without impacting animal survival, while sustainably expressing lentivirally encoded transgenes. We hypothesize that IL-7 secreted by GEMs will increase proliferation and survival of these therapeutic CAR T cells, and enhance anti-tumor activity.
Credits: None available.
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