Antigen-presenting cell-mimetic scaffolds and methods for making and using the same

Abstract

Embodiments herein described provide antigen-presenting cell-mimetic scaffolds (APC-MS) and use of such scaffolds to manipulating T-cells. More specifically, the scaffolds are useful for promoting growth, division, differentiation, expansion, proliferation, activity, viability, exhaustion, anergy, quiescence, apoptosis, or death of T-cells in various settings, e.g., in vitro, ex vivo, or in vivo. Embodiments described herein further relate to pharmaceutical compositions, kits, and packages containing such scaffolds. Additional embodiments relate to methods for making the scaffolds, compositions, and kits/packages. Also described herein are methods for using the scaffolds, compositions, and/or kits in the diagnosis or therapy of diseases such as cancers, immunodeficiency disorders, and/or autoimmune disorders.

1 .- 95 . (canceled) 
     
     
         96 . A method for the manipulation of T cells, comprising contacting an antigen presenting cell-mimetic scaffold (APC-MS) with a biological sample comprising T cells, wherein the APC-MS comprises:
 high surface area mesoporous silica micro-rods (MSR), wherein spaces between the MSR permit T cell infiltration;   a fluid supported lipid bilayer (SLB) layered on the MSR; and   a functional molecule selected from the group consisting of a T-cell activating molecule, a T cell co-stimulatory molecule, and a combination thereof, wherein the functional molecule is presented on the SLB.   
     
     
         97 . The method of  claim 96 , wherein the T cells in the sample comprise exhausted T cells. 
     
     
         98 . The method of  claim 97 , wherein the exhausted T cells are CD8+PD-1+ and/or LAG-3+TIM-3+. 
     
     
         99 . The method of  claim 96 , further comprising detecting the expression of one or more cell-surface markers in the manipulated T cells. 
     
     
         100 . The method of  claim 99 , wherein at least one of the cell surface markers is selected from the group consisting of CD4, CD8, CD25, CD28, CD36, CD40, CD44, CD45, CD62L, CD69, CD134, FOXP3, 4-1BB, LAG-3, TIM-3, and PD-1. 
     
     
         101 . The method of  claim 96 , wherein the biological sample is obtained from a subject and the APC-MS is contacted with the biological sample ex vivo. 
     
     
         102 . The method of  claim 96 , wherein the T cells are selected from the group consisting of natural killer T cells, gamma delta T cells, CD3+ T cells, CD4+ T cells, CD8+ T cells, regulatory T cells (Tregs), tumor-infiltrating lymphocytes, and a combination thereof. 
     
     
         103 . The method of  claim 96 , wherein the T cells comprise Tregs selected from the group consisting of FOXP3+ Tregs, FOXP3-Tregs, and a combination thereof. 
     
     
         104 . The method of  claim 96 , wherein the T cells are manipulated to generate an expanded population of effector memory, effector, central memory, and/or naïve T cells. 
     
     
         105 . The method of  claim 96 , wherein the manipulated T cells comprise CD8+ cells, CD4+ cells, CD4+/FOXP3− T cells, CD44+/CD62L− T cells, CD8+/CD69+ T cells, granzyme B+ CD8+ T cells, and/or IFN-γ-producing T cells. 
     
     
         106 . The method of  claim 96 , wherein the APC-MS comprises a T-cell homeostatic agent. 
     
     
         107 . The method of  claim 106 , wherein the T-cell homeostatic agent is loaded onto the MSR. 
     
     
         108 . The method of  claim 96 , wherein the APC-MS comprises both the T-cell activating molecule and the T-cell co-stimulatory molecule. 
     
     
         109 . The method of  claim 96 , wherein the T-cell activating molecule, or the T-cell co-stimulatory molecule, or both, are presented on the SLB via affinity pairing or chemical coupling. 
     
     
         110 . The method of  claim 96 , wherein the APC-MS comprises an immunoglobulin molecule that binds specifically to an Fc-fusion protein, wherein the immunoglobulin molecule is presented on the SLB. 
     
     
         111 . The method of  claim 96 , wherein the APC-MS further comprises a recruitment compound selected from the group consisting of granulocyte macrophage-colony stimulating factor (GM-CSF), chemokine (C-C motif) ligand 21 (CCL-21), chemokine (C-C motif) ligand 19 (CCL 19), Chemokine (C-X-C Motif) ligand 12 (CXCL12), interferon gamma (IFNγ), an FMS like tyrosine kinase 3 (Flt-3) ligand, and a combination thereof. 
     
     
         112 . The method of  claim 111 , wherein the recruitment compound comprises GM-CSF. 
     
     
         113 . The method of  claim 96 , wherein the APC-MS comprises an antigen presented on the SLB. 
     
     
         114 . The method of  claim 96 , wherein the dry weight ratio of the MSR to the T-cell activating molecule, or the T-cell co-stimulatory molecule, or both if both are present, is between 200:1 to 20:1. 
     
     
         115 . The method of  claim 96 , wherein the spaces between the MSR that permit T cell infiltration have a mean diameter of 6.8 μm to 12 μm. 
     
     
         116 . The method of  claim 96 , wherein the MSR comprise a length of 50 μm to 200 μm. 
     
     
         117 . The method of  claim 96 , wherein the MSR comprise a length of 80 μm to 120 μm. 
     
     
         118 . The method of  claim 96 , wherein the MSR comprise an average length of 100 μm. 
     
     
         119 . The method of  claim 96 , wherein the MSR comprise an average length of 88 μm. 
     
     
         120 . The method of  claim 118 , wherein the MSR comprise an average diameter of 4.5 μm. 
     
     
         121 . The method of  claim 96 , wherein the MSR comprise an aspect ratio of 20. 
     
     
         122 . The method of  claim 96 , wherein the weight ratio of the SLB to the MSR is between 1:4 and 1:20. 
     
     
         123 . The method of  claim 96 , wherein the biological sample is a blood sample, a bone marrow sample, a lymphatic sample, or a splenic sample obtained from a human. 
     
     
         124 . The method of  claim 96 , wherein the manipulation results in improved differentiation, expansion, or activity; and/or reduced exhaustion, anergy, or death of the T cells.