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

Abstract

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.

Materials for Immunotherapy

“…Soon after, the same group developed ICMVs loaded with the topoisomerase I drug SN‐38 and bound to T cells for trafficking into solid lymphomas (Figure a–d) . Recently, the Irvine group extended this concept to create protein nanogels that selectively release IL‐15 in response to T cell activation via reductions in surface potential after antigen recognition . In summary, given the multifaceted ways in which lymphocytes respond to inflammation, the concept of particle backpacking remains a promising area for innovation.…”

Hybridoma technology: the preferred method for monoclonal antibody generation for in vivo applications

“…Once the ScFv interacts with the TAA, the T cell becomes activated and initiates an immune response directly targeting the tumor. Novel forms of targeted biologics are being discovered every day, such as bispecific CARs and T-cell receptor therapy [13]. With ADCs and targeted biologics on the rise, there is no telling what astounding discovery will revolutionize mAb therapeutics next.…”

CAR T cells for brain tumors: Lessons learned and road ahead

“…IL‐12− and IL‐18−secreting CAR T cells have thus been shown to persist longer and lead to enhanced tumor responses in preclinical models of solid cancers . Other investigators have described improved anti‐tumor efficiencies of CAR T cells equipped with constitutive IL‐7 and IL‐15 signaling, as well as by inducible delivery of an IL‐15 super‐agonist complex by T cells upon encounter with the cognate antigen . Approaches involving secretion of pro‐inflammatory molecules may have additional paracrine effects, eg, remodeling the TME and activating by‐stander immune cells such as tumor‐associated macrophages.…”