A carbon nanotube–polymer composite for T-cell therapy
Source abstract
Abstract
Clinical translation of cell therapies requires strategies that can manufacture cells efficiently and economically. One promising way to reproducibly expand T cells for cancer therapy is by attaching the stimuli for T cells onto artificial substrates with high surface area. Here, we show that a carbon nanotube-polymer composite can act as an artificial antigen-presenting cell to efficiently expand the number of T cells isolated from mice. We attach antigens onto bundled carbon nanotubes and combined this complex with polymer nanoparticles containing magnetite and the T-cell growth factor interleukin-2 (IL-2). The number of T cells obtained was comparable to clinical standards using a thousand-fold less soluble IL-2. T cells obtained from this expansion were able to delay tumour growth in a murine model for melanoma. Our results show that this composite is a useful platform for generating large numbers of cytotoxic T cells for cancer immunotherapy.
Source: europepmc · Quality: candidate unverified · Source record ↗
Research context
OpenAlex topics: CAR-T cell therapy research · Immunotherapy and Immune Responses · Immune Cell Function and Interaction
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
References (45)
Show source-provided references
1. Waldmann, T. A. Immunotherapy: past, present and future. Nature Med. 9, 269–277 (2003).10.1038/nm0303-269 ↗
2. Dudley, M. E. & Rosenberg, S. A. Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nature Rev. Cancer 3, 666–675 (2003).10.1038/nrc1167 ↗
3. Zemon, H. An artificial solution for adoptive immunotherapy. Trends Biotechnol. 21, 418–420 (2003).10.1016/j.tibtech.2003.08.005 ↗
4. Brentjens, R. J. et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Science Transl. Med. 5, 177ra38 (2013).10.1126/scitranslmed.3005930 ↗
5. Robbins, P. F. et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J. Clin. Oncol. 29, 917–924 (2011).10.1200/JCO.2010.32.2537 ↗
6. Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).10.1056/NEJMoa1215134 ↗
7. Murphy, K., Travers, P. & Walport, M. Janeway's Immunobiology (Garland Science, 2008).
8. Kim, J. V., Latouche, J.-B., Rivière, I. & Sadelain, M. The ABCs of artificial antigen presentation. Nature Biotechnol. 22, 403–410 (2004).10.1038/nbt955 ↗
9. Steenblock, E. R., Wrzesinski, S. H., Flavell, R. A. & Fahmy, T. M. Antigen presentation on artificial acellular substrates: modular systems for flexible, adaptable immunotherapy. Expert Opin. Biol. Ther. 9, 451–464 (2009).10.1517/14712590902849216 ↗
10. Kropshofer, H. et al. Tetraspan microdomains distinct from lipid rafts enrich select peptide-MHC class II complexes. Nature Immunol. 3, 61–68 (2002).10.1038/ni750 ↗
11. Fooksman, D. R., Grönvall, G. K., Tang, Q. & Edidin, M. Clustering class I MHC modulates sensitivity of T cell recognition. J. Immunol. 176, 6673–6680 (2006).10.4049/jimmunol.176.11.6673 ↗
12. Andersen, P. S., Menné, C., Mariuzza, R. A., Geisler, C. & Karjalainen, K. A response calculus for immobilized T cell receptor ligands. J. Biol. Chem. 276, 49125–49132 (2001).10.1074/jbc.M109396200 ↗
13. González, P. A. et al. T cell receptor binding kinetics required for T cell activation depend on the density of cognate ligand on the antigen-presenting cell. Proc. Natl Acad. Sci. USA 102, 4824–4829 (2005).10.1073/pnas.0500922102 ↗
14. Grakoui, A. et al. The immunological synapse: a molecular machine controlling T cell activation. Science 285, 221–227 (1999).10.1126/science.285.5425.221 ↗
15. Monks, C. R., Freiberg, B. A., Kupfer, H., Sciaky, N. & Kupfer, A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395, 82–86 (1998).10.1038/25764 ↗
16. Cemerski, S. et al. The stimulatory potency of T cell antigens is influenced by the formation of the immunological synapse. Immunity 26, 345–355 (2007).10.1016/j.immuni.2007.01.013 ↗
17. Li, Q.-J. et al. CD4 enhances T cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse. Nature Immunol. 5, 791–799 (2004).10.1038/ni1095 ↗
18. Oelke, M. et al. Ex vivo induction and expansion of antigen-specific cytotoxic T cells by HLA-Ig-coated artificial antigen-presenting cells. Nature Med. 9, 619–624 (2003).10.1038/nm869 ↗
19. Prakken, B. et al. Artificial antigen-presenting cells as a tool to exploit the immune 'synapse'. Nature Med. 6, 1406–1410 (2000).10.1038/82231 ↗
20. Zitvogel, L. et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell derived exosomes. Nature Med. 4, 594–600 (1998).10.1038/nm0598-594 ↗
21. Steenblock, E. R. & Fahmy, T. M. A comprehensive platform for ex vivo T-cell expansion based on biodegradable polymeric artificial antigen-presenting cells. Mol. Ther. 16, 765–772 (2008).10.1038/mt.2008.11 ↗
22. Oosten, L. E. M. et al. Artificial antigen-presenting constructs efficiently stimulate minor histocompatibility antigen-specific cytotoxic T lymphocytes. Blood 104, 224–226 (2004).10.1182/blood-2003-07-2461 ↗
23. Sabatos, C. A. et al. A synaptic basis for paracrine interleukin-2 signaling during homotypic T cell interaction. Immunity 29, 238–248 (2008).10.1016/j.immuni.2008.05.017 ↗
24. Huse, M., Quann, E. J. & Davis, M. M. Shouts, whispers and the kiss of death: directional secretion in T cells. Nature Immunol. 9, 1105–1111 (2008).10.1038/ni.f.215 ↗
25. Ye, Q. et al. Engineered artificial antigen presenting cells facilitate direct and efficient expansion of tumor infiltrating lymphocytes. J. Transl. Med. 9, 131 (2011).10.1186/1479-5876-9-131 ↗
26. Malek, T. R. The biology of interleukin-2. Annu. Rev. Immunol. 26, 453–479 (2008).10.1146/annurev.immunol.26.021607.090357 ↗
27. Fadel, T. R. & Fahmy, T. M. Immunotherapy applications of carbon nanotubes: from design to safe applications. Trends Biotechnol. 32, 198–209 (2014).10.1016/j.tibtech.2014.02.005 ↗
28. Zanello, L. P., Zhao, B., Hu, H. & Haddon, R. C. Bone cell proliferation on carbon nanotubes. Nano Lett. 6, 562–567 (2006).10.1021/nl051861e ↗
29. Nayak, T. R. et al. Thin films of functionalized multiwalled carbon nanotubes as suitable scaffold materials for stem cells proliferation and bone formation. ACS Nano 4, 7717–7725 (2010).10.1021/nn102738c ↗
30. Steenblock, E. R., Fadel, T., Labowsky, M., Pober, J. S. & Fahmy, T. M. An artificial antigen-presenting cell with paracrine delivery of IL-2 impacts the magnitude and direction of the T cell response. J. Biol. Chem. 286, 34883–34892 (2011).10.1074/jbc.M111.276329 ↗
31. Chen, Y. et al. Low-defect, purified, narrowly (n,m)-dispersed single-walled carbon nanotubes grown from cobalt-incorporated MCM-41. ACS Nano 1, 327–336 (2007).10.1021/nn700106c ↗
32. Fadel, T. R. et al. Enhanced cellular activation with single walled carbon nanotube bundles presenting antibody stimuli. Nano Lett. 8, 2070–2076 (2008).10.1021/nl080332i ↗
33. Fadel, T. R. et al. Adsorption of multimeric T cell antigens on carbon nanotubes: effect on protein structure and antigen-specific T cell stimulation. Small 9, 666–672 (2013).10.1002/smll.201201684 ↗
34. Hogquist, K. A. et al. T cell receptor antagonist peptides induce positive selection. Cell 76, 17–27 (1994).10.1016/0092-8674(94)90169-4 ↗
35. Fadel, T. R. et al. Clustering of stimuli on single-walled carbon nanotube bundles enhances cellular activation. Langmuir 26, 5645–5654 (2010).10.1021/la902068z ↗
36. Park, J. et al. Enhancement of surface ligand display on PLGA nanoparticles with amphiphilic ligand conjugates. J. Control. Rel. 156, 109–115 (2011).10.1016/j.jconrel.2011.06.025 ↗
37. Fahmy, T. M., Samstein, R. M., Harness, C. C. & Mark Saltzman, W. Surface modification of biodegradable polyesters with fatty acid conjugates for improved drug targeting. Biomaterials 26, 5727–5736 (2005).10.1016/j.biomaterials.2005.02.025 ↗
38. Ragheb, R. R. T. et al. Induced clustered nanoconfinement of superparamagnetic iron oxide in biodegradable nanoparticles enhances transverse relaxivity for targeted theranostics. Magn. Reson. Med. 70, 1748–1760 (2013).10.1002/mrm.24622 ↗
39. Cheng, L. E., Ohlén, C., Nelson, B. H. & Greenberg, P. D. Enhanced signaling through the IL-2 receptor in CD8+ T cells regulated by antigen recognition results in preferential proliferation and expansion of responding CD8+ T cells rather than promotion of cell death. Proc. Natl Acad. Sci. USA 99, 3001–3006 (2002).10.1073/pnas.052676899 ↗
40. Labowsky, M. & Fahmy, T. M. Diffusive transfer between two intensely interacting cells with limited surface kinetics. Chem. Eng. Sci. 74, 114–123 (2012).10.1016/j.ces.2012.02.001 ↗
41. Janas, M. L., Groves, P., Kienzle, N. & Kelso, A. IL-2 regulates perforin and granzyme gene expression in CD8+ T cells independently of its effects on survival and proliferation. J. Immunol. 175, 8003–8010 (2005).10.4049/jimmunol.175.12.8003 ↗
42. Rabinovich, G. A., Gabrilovich, D. & Sotomayor, E. M. Immunosuppressive strategies that are mediated by tumor cells. Annu. Rev. Immunol. 25, 267–296 (2007).10.1146/annurev.immunol.25.022106.141609 ↗
43. Pardoll, D. M. Spinning molecular immunology into successful immunotherapy. Nature Rev. Immunol. 2, 227–238 (2002).10.1038/nri774 ↗
44. Suter, D. M. & Krause, K-H. Neural commitment of embryonic stem cells: molecules, pathways and potential for cell therapy. J. Pathol. 215, 355–368 (2008).10.1002/path.2380 ↗
45. McIntosh, K. et al. The immunogenicity of human adipose-derived cells: temporal changes in vitro. Stem Cells 24, 1246–1253 (2006).10.1634/stemcells.2005-0235 ↗