Lyophilized lymph nodes for improved delivery of chimeric antigen receptor T cells
Source abstract
Abstract
Lymph nodes are crucial organs of the adaptive immune system, orchestrating T cell priming, activation and tolerance. T cell activity and function are highly regulated by lymph nodes, which have a unique structure harbouring distinct cells that work together to detect and respond to pathogen-derived antigens. Here we show that implanted patient-derived freeze-dried lymph nodes loaded with chimeric antigen receptor T cells improve delivery to solid tumours and inhibit tumour recurrence after surgery. Chimeric antigen receptor T cells can be effectively loaded into lyophilized lymph nodes, whose unaltered meshwork and cytokine and chemokine contents promote chimeric antigen receptor T cell viability and activation. In mouse models of cell-line-derived human cervical cancer and patient-derived pancreatic cancer, delivery of chimeric antigen receptor T cells targeting mesothelin via the freeze-dried lymph nodes is more effective in preventing tumour recurrence when compared to hydrogels containing T-cell-supporting cytokines. This tissue-mediated cell delivery strategy holds promise for controlled release of various cells and therapeutics with long-term activity and augmented function.
Source: europepmc · Quality: candidate unverified · Source record ↗
Research context
OpenAlex topics: CAR-T cell therapy research · Virus-based gene therapy research · Viral Infectious Diseases and Gene Expression in Insects
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
References (54)
Show source-provided references
1. Brentjens, R. J. et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med. 5, 177ra138 (2013).10.1126/scitranslmed.3005930 ↗
2. Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).10.1056/NEJMoa1407222 ↗
3. Hou, A. J., Chen, L. C. & Chen, Y. Y. Navigating CAR T cells through the solid-tumour microenvironment. Nat. Rev. Drug Discov. 20, 531–550 (2021).10.1038/s41573-021-00189-2 ↗
4. Milone, M. C. et al. Engineering-enhanced CAR T cells for improved cancer therapy. Nat. Cancer 2, 780–793 (2021).10.1038/s43018-021-00241-5 ↗
5. Hong, M., Clubb, J. D. & Chen, Y. Y. Engineering CAR T cells for next-generation cancer therapy. Cancer Cell 38, 473–488 (2020).10.1016/j.ccell.2020.07.005 ↗
6. Rafiq, S., Hackett, C. S. & Brentjens, R. J. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat. Rev. Clin. Oncol. 17, 147–167 (2020).10.1038/s41571-019-0297-y ↗
7. Labanieh, L., Majzner, R. G. & Mackall, C. L. Programming CAR T cells to kill cancer. Nat. Biomed. Eng. 2, 377–391 (2018).10.1038/s41551-018-0235-9 ↗
8. Fu, R. et al. Delivery techniques for enhancing CAR T cell therapy against solid tumors. Adv. Funct. Mater. 31, 2009489 (2021).10.1002/adfm.202009489 ↗
9. Wang, H. & Mooney, D. J. Biomaterial-assisted targeted modulation of immune cells in cancer treatment. Nat. Mater. 17, 761–772 (2018).10.1038/s41563-018-0147-9 ↗
10. Hu, Q. et al. Inhibition of post-surgery tumour recurrence via a hydrogel releasing CAR T cells and anti-PDL1-conjugated platelets. Nat. Biomed. Eng. 5, 1038–1047 (2021).10.1038/s41551-021-00712-1 ↗
11. Stephan, S. B. et al. Biopolymer implants enhance the efficacy of adoptive T cell therapy. Nat. Biotechnol. 33, 97–101 (2015).10.1038/nbt.3104 ↗
12. Pérez del Río, E. et al. CCL21-loaded 3D hydrogels for T cell expansion and differentiation. Biomaterials 259, 120313 (2020).10.1016/j.biomaterials.2020.120313 ↗
13. Suematsu, S. & Watanabe, T. Generation of a synthetic lymphoid tissue-like organoid in mice. Nat. Biotechnol. 22, 1539–1545 (2004).10.1038/nbt1039 ↗
14. Cheung, A. S., Zhang, D. K. Y., Koshy, S. T. & Mooney, D. J. Scaffolds that mimic antigen-presenting cells enable ex vivo expansion of primary T cells. Nat. Biotechnol. 36, 160–169 (2018).10.1038/nbt.4047 ↗
15. Coon, M. E., Stephan, S. B., Gupta, V., Kealey, C. P. & Stephan, M. T. Nitinol thin films functionalized with CAR T cells for the treatment of solid tumours. Nat. Biomed. Eng. 4, 195–206 (2020).10.1038/s41551-019-0486-0 ↗
16. Grosskopf, A. K. et al. Delivery of CAR T cells in a transient injectable stimulatory hydrogel niche improves treatment of solid tumors. Sci. Adv. 8, eabn8264 (2022).10.1126/sciadv.abn8264 ↗
17. Wang, K. et al. GD2-specific CAR T cells encapsulated in an injectable hydrogel control retinoblastoma and preserve vision. Nat. Cancer 1, 990–997 (2020).10.1038/s43018-020-00119-y ↗
18. Ma, L. et al. Enhanced CAR T cell activity against solid tumors by vaccine boosting through the chimeric receptor. Science 365, 162–168 (2019).10.1126/science.aav8692 ↗
19. Krishnamurty, A. T. & Turley, S. J. Lymph node stromal cells: cartographers of the immune system. Nat. Immunol. 21, 369–380 (2020).10.1038/s41590-020-0635-3 ↗
20. Bousso, P. T cell activation by dendritic cells in the lymph node: lessons from the movies. Nat. Rev. Immunol. 8, 675–684 (2008).10.1038/nri2379 ↗
21. Saxena, V. et al. Role of lymph node stroma and microenvironment in T cell tolerance. Immunol. Rev. 292, 9–23 (2019).10.1111/imr.12799 ↗
22. Cyster, J. G. Chemokines and cell migration in secondary lymphoid organs. Science 286, 2098–2102 (1999).10.1126/science.286.5447.2098 ↗
23. von Andrian, U. H. & Mempel, T. R. Homing and cellular traffic in lymph nodes. Nat. Rev. Immunol. 3, 867–878 (2003).10.1038/nri1222 ↗
24. Morton, D. L. et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N. Engl. J. Med. 370, 599–609 (2014).10.1056/NEJMoa1310460 ↗
25. Leone, A., Diorio, G. J., Pettaway, C., Master, V. & Spiess, P. E. Contemporary management of patients with penile cancer and lymph node metastasis. Nat. Rev. Urol. 14, 335–347 (2017).10.1038/nrurol.2017.47 ↗
26. Cochran, A. J. et al. Tumour-induced immune modulation of sentinel lymph nodes. Nat. Rev. Immunol. 6, 659–670 (2006).10.1038/nri1919 ↗
27. Zhang, C. et al. Mapping the spreading routes of lymphatic metastases in human colorectal cancer. Nat. Commun. 11, 1993 (2020).10.1038/s41467-020-15886-6 ↗
28. Tasnim, H. et al. Quantitative measurement of naïve T cell association with dendritic cells, FRCs, and blood vessels in lymph nodes. Front. Immunol. 9, 1571 (2018).10.3389/fimmu.2018.01571 ↗
29. Liu, W. F. et al. Real-time in vivo detection of biomaterial-induced reactive oxygen species. Biomaterials 32, 1796–1801 (2011).10.1016/j.biomaterials.2010.11.029 ↗
30. Vella, A. T., Dow, S., Potter, T. A., Kappler, J. & Marrack, P. Cytokine-induced survival of activated T cells in vitro and in vivo. Proc. Natl Acad. Sci. USA 95, 3810–3815 (1998).10.1073/pnas.95.7.3810 ↗
31. Hermans, D. et al. Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8+ T cell stemness and antitumor immunity. Proc. Natl Acad. Sci. USA 117, 6047–6055 (2020).10.1073/pnas.1920413117 ↗
32. Castro, F., Cardoso, A. P., Gonçalves, R. M., Serre, K. & Oliveira, M. J. Interferon-gamma at the crossroads of tumor immune surveillance or evasion. Front. Immunol. 9, 847 (2018).10.3389/fimmu.2018.00847 ↗
33. Assarsson, E. et al. Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS ONE 9, e95192 (2014).10.1371/journal.pone.0095192 ↗
34. Onder, L. et al. IL-7–producing stromal cells are critical for lymph node remodeling. Blood 120, 4675–4683 (2012).10.1182/blood-2012-03-416859 ↗
35. Mueller, S. N. & Germain, R. N. Stromal cell contributions to the homeostasis and functionality of the immune system. Nat. Rev. Immunol. 9, 618–629 (2009).10.1038/nri2588 ↗
36. Gattinoni, L., Speiser, D. E., Lichterfeld, M. & Bonini, C. T memory stem cells in health and disease. Nat. Med. 23, 18–27 (2017).10.1038/nm.4241 ↗
37. Mahnke, Y. D., Brodie, T. M., Sallusto, F., Roederer, M. & Lugli, E. The who’s who of T cell differentiation: human memory T cell subsets. Eur. J. Immunol. 43, 2797–2809 (2013).10.1002/eji.201343751 ↗
38. Schluns, K. S., Kieper, W. C., Jameson, S. C. & Lefrançois, L. Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo. Nat. Immunol. 1, 426–432 (2000).10.1038/80868 ↗
39. Geginat, J., Sallusto, F. & Lanzavecchia, A. Cytokine-driven proliferation and differentiation of human naive, central memory, and effector memory CD4+ T cells. J. Exp. Med. 194, 1711–1720 (2001).10.1084/jem.194.12.1711 ↗
40. Grabstein, K. H. et al. Cloning of a T cell growth factor that interacts with the β chain of the interleukin-2 receptor. Science 264, 965–968 (1994).10.1126/science.8178155 ↗
41. Schluns, K. S. & Lefrançois, L. Cytokine control of memory T cell development and survival. Nat. Rev. Immunol. 3, 269–279 (2003).10.1038/nri1052 ↗
42. Melenhorst, J. J. et al. Decade-long leukaemia remissions with persistence of CD4+ CAR T cells. Nature 602, 503–509 (2022).10.1038/s41586-021-04390-6 ↗
43. Propper, D. J. & Balkwill, F. R. Harnessing cytokines and chemokines for cancer therapy. Nat. Rev. Clin. Oncol. 19, 237–253 (2022).10.1038/s41571-021-00588-9 ↗
44. Briukhovetska, D. et al. Interleukins in cancer: from biology to therapy. Nat. Rev. Cancer 21, 481–499 (2021).10.1038/s41568-021-00363-z ↗
45. Kagoya, Y. et al. A novel chimeric antigen receptor containing a JAK–STAT signaling domain mediates superior antitumor effects. Nat. Med. 24, 352–359 (2018).10.1038/nm.4478 ↗
46. Hurton, L. V. et al. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells. Proc. Natl Acad. Sci. USA 113, E7788–E7797 (2016).10.1073/pnas.1610544113 ↗
47. Tang, L. et al. Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery. Nat. Biotechnol. 36, 707–716 (2018).10.1038/nbt.4181 ↗
48. Liu, Y. et al. Cytokine conjugation to enhance T cell therapy. Proc. Natl Acad. Sci. USA 120, e2213222120 (2023).10.1073/pnas.2213222120 ↗
49. Li, A. M. et al. Checkpoint inhibitors augment CD19-directed chimeric antigen receptor (CAR) T cell therapy in relapsed B cell acute lymphoblastic leukemia. Blood 132, 556 (2018).10.1182/blood-2018-99-112572 ↗
50. Zhang, J. et al. Non-viral, specifically targeted CAR T cells achieve high safety and efficacy in B-NHL. Nature 609, 369–374 (2022).10.1038/s41586-022-05140-y ↗
51. Link, A. et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat. Immunol. 8, 1255–1265 (2007).10.1038/ni1513 ↗
52. Horsnell, H. L. et al. Lymph node homeostasis and adaptation to immune challenge resolved by fibroblast network mechanics. Nat. Immunol. 23, 1169–1182 (2022).10.1038/s41590-022-01272-5 ↗
53. Nam, S., Seo, B. R., Najibi, A. J., McNamara, S. L. & Mooney, D. J. Active tissue adhesive activates mechanosensors and prevents muscle atrophy. Nat. Mater. 22, 249–259 (2023).10.1038/s41563-022-01396-x ↗
54. Gong, N. et al. In situ PEGylation of CAR T cells alleviates cytokine release syndrome and neurotoxicity. Nat. Mater. 22, 1571–1580 (2023).10.1038/s41563-023-01646-6 ↗