The overall goal of this project is to create the next generation biomimetic artificial antigen presenting cells (aAPCs) for T-Cell based melanoma immunotherapy. Metastatic melanoma is major health concern with increasing prevalence and a poor 5 year survival rate. Adoptive T-Cell immunotherapy stands to be a promising strategy to treat advanced melanomas, however current techniques for activation and culture of tumor targeting T-Cells remain prohibitively expensive for widespread acceptance of the therapy. Therefore, there is a need for affordable ?off-the-shelf? methods to stimulate T-Cells for cancer immunotherapy both ex vivo and in vivo. Artificial antigen presenting cells (aAPCs) can serve in this capacity. Through conjugation of critical Signal 1 and Signal 2 proteins to the surface of a synthetic particle, aAPCs have shown the potential to generate large quantities of antigen specific cytotoxic T-Cells ex vivo with anti-tumor activity. However, these particles remain relatively ineffective with regard to stimulation of adoptively transferred or endogenous anti- tumor T-Cells in vivo compared to equivalent autologous antigen presenting cell platforms. Current data supports the notion that these aAPC do not effectively mimic the complex morphological and surface receptor organizational changes that an APC undergoes during engagement with a cognate T-Cell. We have successfully demonstrated that non-spherical, prolate ellipsoidal aAPCs mediate significantly stronger T-Cell activation as evidenced through in vitro T-Cell stimulation and in vivo tumor prevention. Based on our preliminary mechanistic studies we believe this increased activation is due to the enlarged radius of curvature and available surface area presented by ellipsoidal aAPC, compared to spherical aAPC which afford minimal contact with the lymphocyte. This increased available surface area is directly mimetic of the morphological change that an APC undergoes during T-Cell engagement. We therefore hypothesize increasing the biomimicry of the aAPC will simultaneously increase the T-Cell stimulation potential. We hypothesize increasing the surface area and radius of curvature of the particle through deformation into various shapes will mimic the APC morphological change. We also hypothesize presentation of the proteins on a fluidic supported lipid bilayer will enable dynamic rearrangement of aAPC/TCR receptor complexes in direct mimicry of the immunological synapse.
In Specific Aim 1 we will engineer these multiple layers of biomimicry into a single particle and characterize their biophysical properties.
In Specific Aim 2 we will demonstrate the effectiveness of these particles in stimulation of T-Cells as well as characterize T-Cell effector function ex vivo. Finally, in Specific Aim 3 we will characterize the in vivo biodistribution of these aAPCs when administered with T-Cells as well as the anti-tumor efficacy of the aAPC combined with immune checkpoint blockades in an adoptive immunotherapy model. Successful completion of this work will enable us to characterize and implement a potent and affordable therapeutic for melanoma immunotherapy.
The research described in this proposal aims to develop new materials that mimic key immune cells in the human body with a high degree of accuracy. These artificial cells can trigger the immune system to mount a specific attack on cancer cells, and the particular application in this proposal is melanoma. This technology has the potential to treat individuals with advanced melanomas and prevent tumor recurrence, thereby significantly extending survival of these patients.
| Meyer, Randall A; Mathew, Mohit P; Ben-Akiva, Elana et al. (2018) Anisotropic biodegradable lipid coated particles for spatially dynamic protein presentation. Acta Biomater 72:228-238 |
| Ben-Akiva, Elana; Meyer, Randall A; Wilson, David R et al. (2017) Surface engineering for lymphocyte programming. Adv Drug Deliv Rev 114:102-115 |
| Kosmides, A K; Meyer, R A; Hickey, J W et al. (2017) Biomimetic biodegradable artificial antigen presenting cells synergize with PD-1 blockade to treat melanoma. Biomaterials 118:16-26 |
