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Abstract
Background T cell-based immunotherapies such as chimeric antigen receptor T cell therapy (CAR T), have seen some clinical success; however, these therapies are still currently limited to a select few cancer types and have price tags that further limit accessibility for patients. Here, we create a novel biomaterials-based platform for the in vivo activation of naïve, antigen-specific T cells, removing the need for expensive and lengthy ex vivo expansion steps.
Methods Thiol-modified HA is cross-linked with PEDGA in the presence of thiol-modified signals 1 (here, KbOVA) and 2 (anti CD28).1 The cross-linked gel is passed through a mesh to form microparticles (MPs) (figure 1A). MPs are mixed with naïve B6 CD8+ T cells and injected subcutaneously into mice. Eight days after injection, target cells expressing OVA antigen are injected i.v. On day 9, mice are sacrificed and analyzed for enrichment of antigen-specific cells and killing of target cells. MPs were also tested therapeutic tumor model, in which MC-38 OVA tumor cells were injected on day 0 and naïve OT I CD8s plus MPs were injected on day 6.
Results Nine days after co-injecting naïve B6 CD8+ T cells with KbOVA MPs, we can detect a significant enrichment of OVA-specific T cells via flow cytometry (figure 1B). Cells expanded in vivo showed significant and robust killing of target splenocytes (figure 1C). In the MC-38 OVA cancer treatment model, injection of naïve OT I CD8+ T cells with OVA MPs increased survival compared with naïve OT I CD8+ cells injected with blank MPs (figure 1D).
Conclusions We have developed an injectable, LN-mimicking MP platform that incorporates T-cell activation signals and critical ECM cues of the LN. These MPs are capable of expanding antigen-specific T cells from a fully endogenous B6 repertoire, and these cells are able to robustly kill target splenocytes as well as reduce tumor growth and extend survival in a therapeutic cancer model. Developing a system for the in vivo activation of antigen-specific T cells reduces both cost of T cell-based therapies as well as the time to treatment for patients.
Acknowledgements NKL is supported by the NSF GRFP and NIH F31 Fellowships.
Reference
Hickey JW, Dong Y, Chung JW, Salathe SF, Pruitt HC, Li X, Chang C, Fraser AK, Bessell CA, Ewald AJ, Gerecht S, Mao H, Schneck JP. Engineering an Artificial T-Cell Stimulating Matrix for Immunotherapy. Adv Mater. 2019; Apr 10;1807359.
(A) Schematic of the preparation of T cell-stimulating MPs. (B) Enrichment of OVA-specific T cells within the biomaterial site 9 days after injection. (C) In vivo killing of OVA-pulsed splenocytes after 9 days of in vivo expansion of OVA-specific T cells. (D) Survival plot after mice are injected with MC-38 OVA tumor cells on day 0 and naïve OT I CD8s plus MPs on day 6.