Conspectus A major function of the immune system is to detect threat from foreign invaders, tissue damage, or cancer and to mount a counter response that resolves the threat, restores homeostasis, and supplies immunological memory to prevent a second assault. Our increasing understanding of the immune system has opened up numerous avenues for modulating immune responses against infections, cancer, and autoimmunity. However, agents used for immunomodulation have been traditionally administered systemically via bolus injection, leading to unintended consequences by disrupting homeostasis at nontarget sites. Consequently, systemic hyperactivation and hypoactivation can result from bolus administration of immune-activators and immunosuppressants, respectively. Macroscale biomaterial scaffolds can instead be placed at the intended target site to provide both localized, controlled release of immunomodulatory agents and control over local immune cell trafficking and function, potentially maximizing therapeutic efficacy and limiting systemic exposure. These scaffolds have found utility in the area of cancer immunotherapy, especially in situ cancer vaccination where controlled release of factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and the local presentation of tumor antigen and danger signals lead to the recruitment of immature dendritic cells and facilitate their activation and antigen presentation. These cells eventually migrate into secondary lymphoid organs where they prime tumor specific T cells for downstream tumor clearance. Scaffolds can also be used in adoptive T cell therapy to generate large numbers of potent antigen specific T cells or chimeric antigen receptor (CAR) T cells in vitro for subsequent delivery to patients. Macroscale biomaterial scaffolds have also found utility beyond cancer immunotherapy and have been developed to promote immune tolerance by regulatory T cell induction and to expedite tissue regeneration. The design of these macroscale biomaterial scaffolds considers their biocompatibility, biodegradability, mode of delivery, porosity, and kinetics of therapeutic cargo release. Consequently, the numerous approaches that have been developed to fabricate biomaterial scaffolds are aimed at tuning these parameters to achieve the desired therapeutic outcome. This Account will discuss the use of biomaterial scaffolds as niches for immunomodulation and will focus on (1) approaches that have been used to fabricate various biomaterial systems being employed as niches for immunomodulation and (2) how these biomaterial systems have been used to modulate immune responses, specifically in area of cancer immunotherapy, where we will discuss the role of macroscale biomaterial scaffolds for in situ vaccination and in vitro T cell expansion. We will also briefly discuss the utility of biomaterial scaffolds beyond cancer, drawing examples from tolerance and tissue regeneration.

Immunotherapy has had a tremendous impact on cancer treatment in the past decade, with hitherto unseen responses at advanced and metastatic stages of the disease. However, the aggressive brain tumor glioblastoma (GBM) is highly immunosuppressive and remains largely refractory to current immunotherapeutic approaches. The stimulator of interferon genes (STING) DNA sensing pathway has emerged as a next-generation immunotherapy target with potent local immune stimulatory properties. Here, we investigated the status of the STING pathway in GBM and the modulation of the brain tumor microenvironment (TME) with the STING agonist ADU-S100. Our data reveal the presence of STING in human GBM specimens, where it stains strongly in the tumor vasculature. We show that human GBM explants can respond to STING agonist treatment by secretion of inflammatory cytokines. In murine GBM models, we show a profound shift in the tumor immune landscape after STING agonist treatment, with massive infiltration of the tumor-bearing hemisphere with innate immune cells including inflammatory macrophages, neutrophils, and natural killer (NK) populations. Treatment of established murine intracranial GL261 and CT-2A tumors by biodegradable ADU-S100–loaded intracranial implants demonstrated a significant increase in survival in both models and long-term survival with immune memory in GL261. Responses to treatment were abolished by NK cell depletion. This study reveals therapeutic potential and deep remodeling of the TME by STING activation in GBM and warrants further examination of STING agonists alone or in combination with other immunotherapies such as cancer vaccines, chimeric antigen receptor T cells, NK therapies, and immune checkpoint blockade.

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Patient responses to autologous CD19 chimeric antigen receptor (CAR) T-cell therapies are limited by insufficient and inconsistent cellular functionality. Here, we show that controlling the precise level of stimulation during T-cell activation to accommodate individual differences in the donor cells will dictate the functional attributes of CAR-T cell products. The functionality of CAR-T cell products, consisting of a diverse set of blood samples derived from healthy donors, acute lymphoblastic leukemia (ALL), and chronic lymphocytic lymphoma (CLL) patient samples, representing a range of patient health status, is tested upon culturing on artificial antigen-presenting cell scaffolds to deliver T-cell stimulatory ligands (anti-CD3/anti-CD28) at highly defined densities. A clear relationship is observed between the dose of stimulation, the phenotype of the T-cell blood sample prior to T-cell activation, and the functionality of the resulting CAR-T cell products. We present a model, based on this dataset, that predicts the precise stimulation needed to manufacture a desired CAR-T cell product, given the input T-cell attributes in the initial blood sample. These findings demonstrate a simple approach to enhance CAR-T functionality by personalizing the level of stimulation during T-cell activation to enable flexible manufacturing of more consistent and potent CAR-T cells.