(306f) Programming Antitumor Immunity with Nanoscale Architecture

Vaccines potently program the immune system through an adjuvant (activator) and antigen (target), and have been employed to fight various forms of cancer. However, the potential of cancer vaccines has yet to be fully realized, with many vaccine candidates failing out of clinical trials due to a lack of efficacy. These conventional approaches to vaccine design have focused on the composition of the formulation with little consideration for the arrangement of the components on a single vaccine structure. This structural consideration becomes increasingly complex when evaluating the immune landscape necessary for potent tumor remission: to be effective against highly mutative aggressive tumors, cancer vaccines must activate multiple immune cell types. However, design considerations for vaccines capable of targeting multiple different immune cells simultaneously are underexplored. There is therefore a need to evaluate the design space for the structural considerations of multiple antigens on a vaccine specifically in the context of targeting and activating multiple immune cell types effectively.

In this work, we explore the activation of multi-faceted immunity by incorporating numerous antigens targeting various T cell subtypes in defined nanoscale arrangements. We highlight the opportunity to uniquely program immunological interactions and positively impact vaccine efficacy through rational and molecular antigen placement. We have designed a library of compositionally equivalent but structurally distinct multi-antigen vaccines containing targets for both cytotoxic CD8⁺ and helper CD4⁺ T cells. We observed that dendritic cells and both subsets of T cells were altered at the transcripteomic level in response to the different vaccine architectures. A particular architecture led to the upregulation of inflammatory responses and chemotaxis pathways. We determined that key to the different gene expression profiles observed was the nature in which the vaccine architectures were processed in dendritic cells. Nanoscale antigen placement on the vaccine altered the kinetics of processing and processing pathways for the different antigens, and could optimize how each antigen was processed and ultimately presented on dendritic cells for subsequent T cell activation. The immune activity resulting from the changes at the dendritic cell level were propagated into different T cell responses, with T cell activation, antigen-specificity, and proliferation dependent on nanoscale antigen placement on the vaccine. Holistically, this induced system-wide immunity in a structurally-dependent manner. Nanoscale antigen placement influenced antitumor responses in multiple animal models (lymphoma, colon, and melanoma), with one particular architecture stalling tumor growth effectively (<200mm³ through day 24) and potently synergizing with checkpoint inhibitor therapy. Overall, this work highlights how vaccines can be developed to raise complex multi-faceted immunity by manipulating antigen arrangement at the nanoscale.