(311a) Controlling Cellular Phenotypes Via Cytokine-Releasing Backpacks for Cancer Immunotherapy

Immune cells have emerged as a potent therapeutic platform due to their unique homing abilities and highly specific interactions with diseased cells in a way that traditional drugs cannot accomplish. However, unlike traditional drugs, cells are living entities that can alter their function in response to subtle cues from their environment. For example, macrophages, which form a critical component of body’s innate immune system, can dramatically shift their phenotype (i.e., from a proinflammatory M1 type to an anti-inflammatory M2 type) in response to nanomolar levels of cytokine. While such susceptibilities are beneficial in some cases, it has been implicated in several major diseases, including cancer and autoimmune disorders. Thus, as cell-based therapies continue to take hold, there exists a critical and urgent need to develop tools to protect therapeutic immune cells from negative influences in their environment. In this talk, I will introduce a new concept to regulate cellular phenotypes in vivo through cell-binding particle “backpacks”. We study the release of interferon-gamma (IFN-g) as a model cytokine to promote M1 macrophage phenotypes. The backpacks are comprised of poly(lactic-co-glycolic acid) and poly(vinyl alcohol) and are made via microcontact printing. The backpacks are discoidal in shape and are nominally 8 μm across and 1.5 μm thick. By incorporating a cell-binding layer, we show that the backpacks can bind to primary murine macrophages ex vivo in a highly efficient manner and remain surface-bound (without becoming phagocytosed) for at least 48 hours. We show that the backpacks can safely store and release IFN-g (>80 fg/backpack) and polarize macrophages toward M1 phenotypes, as evidenced by a significant upregulation of CD80, MHCII, and iNOS. When injected intratumorally into BALB/c mice bearing 4T1 breast tumors (potentiating an M2-polarizing environment), the backpacks enabled the cells to maintain their M1 polarization for at least 7 days, which led to slowed tumor growth. Looking forward, these cell-binding backpacks have implications in controlling cellular phenotypes to aid in the treatment of cancer, autoimmune disorders, and infectious diseases.