PILOT: Macroporous Scaffolds Functionalized with Tumor Cell Membranes for Multi-Antigenic Cancer Vaccination

ABSTRACT: Cancer vaccines aim to harness the immune system to recognize and eliminate tumor cells through antigen- specific activation of cytotoxic T cells. However, most current cancer vaccine platforms rely on predefined neoantigens that are difficult to identify, costly to manufacture, and poorly suited to address tumor heterogeneity. Tumor cell membranes (TCMs) offer a promising solution, providing a patient-matched, multi- antigenic source that reflects the complex antigenic landscape of individual tumors. However, TCM vaccines delivered via nanoparticles often rely on passive lymphatic drainage, leading to inefficient targeting of antigen- presenting cells (APCs), off-target accumulation, and systemic toxicity. This project proposes a novel strategy that integrates TCMs into a microgel-based macroporous scaffold to create a localized cancer vaccine platform. The scaffold is designed to recruit and activate APCs at the site of implantation, enabling efficient antigen uptake and subsequent T-cell priming. By immobilizing TCMs onto the scaffold surface and incorporating controlled-release adjuvants, the platform offers precise spatiotemporal coordination of antigen and immune activation signals. Our central hypothesis is that macroporous microgel-based scaffolds with optimized porosity and stiffness will promote dendritic cell infiltration and maturation, and that surface-presented TCMs combined with controlled-release adjuvants (MPL and CpG) will elicit robust, multi-antigenic antitumor immune responses. To test this, we propose the following two specific aims: