Engineering Challenges and Opportunities in Autologous Cellular Cancer Immunotherapy.

The use of a patient's own immune or tumor cells, manipulated ex vivo, enables Ag- or patient-specific immunotherapy. Despite some clinical successes, there remain significant barriers to efficacy, broad patient population applicability, and safety. Immunotherapies that target specific tumor Ags, such as chimeric Ag receptor T cells and some dendritic cell vaccines, can mount robust immune responses against immunodominant Ags, but evolving tumor heterogeneity and antigenic downregulation can drive resistance. In contrast, whole tumor cell vaccines and tumor lysate-loaded dendritic cell vaccines target the patient's unique tumor antigenic repertoire without prior neoantigen selection; however, efficacy can be weak when lower-affinity clones dominate the T cell pool. Chimeric Ag receptor T cell and tumor-infiltrating lymphocyte therapies additionally face challenges related to genetic modification, T cell exhaustion, and immunotoxicity. In this review, we highlight some engineering approaches and opportunities to these challenges among four classes of autologous cell therapies.

The cancer glycocalyx mediates intravascular adhesion and extravasation during metastatic dissemination.

The glycocalyx on tumor cells has been recently identified as an important driver for cancer progression, possibly providing critical opportunities for treatment. Metastasis, in particular, is often the limiting step in the survival to cancer, yet our understanding of how tumor cells escape the vascular system to initiate metastatic sites remains limited. Using an in vitro model of the human microvasculature, we assess here the importance of the tumor and vascular glycocalyces during tumor cell extravasation. Through selective manipulation of individual components of the glycocalyx, we reveal a mechanism whereby tumor cells prepare an adhesive vascular niche by depositing components of the glycocalyx along the endothelium. Accumulated hyaluronic acid shed by tumor cells subsequently mediates adhesion to the endothelium via the glycoprotein CD44. Trans-endothelial migration and invasion into the stroma occurs through binding of the isoform CD44v to components of the sub-endothelial extra-cellular matrix. Targeting of the hyaluronic acid-CD44 glycocalyx complex results in significant reduction in the extravasation of tumor cells. These studies provide evidence of tumor cells repurposing the glycocalyx to promote adhesive interactions leading to cancer progression. Such glycocalyx-mediated mechanisms may be therapeutically targeted to hinder metastasis and improve patient survival.