Rethinking Hybridity, Interrogating Mixedness

This article discusses definitions and debates about the terms ‘hybridity’ and ‘mixedness’ across the natural and human and social sciences, including the work of the cultural theorist Homi Bhabha. Using the argonomic idea of homology, that refers to correspondences in both the quality and the states of a thing or phenomena, insights are offered into how we might think of the layers and processes of mixing that can be involved in the event of hybridity. This is particularly important because discussions of mixedness in the social sciences, and in everyday life, can run together different phenomena, strata, states, their sensual traits and their relative maturity or in/stabilities. In the process, different modalities of mixing can be subsumed or collapsed. The article also provides a summary of the key ideas and arguments made by contributors to the issue

Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery

Adoptive cell therapy (ACT) with antigen-specific T cells has shown remarkable clinical success; however, approaches to safely and effectively augment T cell function, especially in solid tumors, remain of great interest. Here we describe a strategy to ‘backpack’ large quantities of supporting protein drugs on T cells by using protein nanogels (NGs) that selectively release these cargos in response to T cell receptor activation. We designed cell surface–conjugated NGs that responded to an increase in T cell surface reduction potential after antigen recognition and limited drug release to sites of antigen encounter, such as the tumor microenvironment. By using NGs that carried an interleukin-15 super-agonist complex, we demonstrated that, relative to systemic administration of free cytokines, NG delivery selectively expanded T cells 16-fold in tumors and allowed at least eightfold higher doses of cytokine to be administered without toxicity. The improved therapeutic window enabled substantially increased tumor clearance by mouse T cell and human chimeric antigen receptor (CAR)-T cell therapy in vivo.Melanoma Research Alliance (Award 306833)National Cancer Institute (U.S.) (Grant P30-CA14051)National Cancer Institute (U.S.) (Grant P30-CA172164