Dextran-based T-cell expansion nanoparticles for manufacturing CAR T cells with augmented efficacy

1. Yu, X. J. et al. Application of CAR-T cell therapy in B-cell lymphoma: a meta-analysis of randomized controlled trials. Clin. Transl. Oncol. 27, 2700–2709 (2025).

   Google Scholar 

2. Raje, N. et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N. Engl. J. Med. 380, 1726–1737 (2019).

   Google Scholar 

3. Park, J. H. et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N. Engl. J. Med. 378, 449–459 (2018).

   Google Scholar 

4. Kandra, P. et al. Utility and drawbacks of chimeric antigen receptor T cell (CAR-T) therapy in Lung cancer. Front. Immunol. 13, 903562 (2022). Article.

   Google Scholar 

5. Ayala Ceja, M., Khericha, M., Harris, C. M., Puig-Saus, C. & Chen, Y. Y. CAR-T cell manufacturing: Major process parameters and next-generation strategies. J. Exp. Med. 221, e20230903 (2024).

   Google Scholar 

6. Agliardi, G., Dias, J., Rampotas, A., Garcia, J. & Roddie, C. Accelerating and optimising CAR T-cell manufacture to deliver better patient products. Lancet Haematol. 12, E57–E67 (2025).

   Google Scholar 

7. Mock, U. et al. Automated manufacturing of chimeric antigen receptor T cells for adoptive immunotherapy using CliniMACS prodigy. Cytotherapy 18, 1002–1011 (2016).

   Google Scholar 

8. Kagoya, Y. et al. Transient stimulation expands superior antitumor T cells for adoptive therapy. JCI Insight 2, e89580 (2017).

9. 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).

   Google Scholar 

10. Zhang, D. K. Y. et al. Subcutaneous biodegradable scaffolds for restimulating the antitumour activity of pre-administered CAR-T cells. Nat. Biomed. Eng. 9, 268–278 (2025).

    Google Scholar 

11. Zhu, E. et al. Biomimetic cell stimulation with a graphene oxide antigen-presenting platform for developing T cell-based therapies. Nat. Nanotechnol. 19, 1914–1922 (2024).

    Google Scholar 

12. Liu, Z. et al. Viscoelastic synthetic antigen-presenting cells for augmenting the potency of cancer therapies. Nat. Biomed. Eng. 8, 1615–1633 (2024).

    Google Scholar 

13. Ariail, E., Garcia Espinoza, N., Stephenson, A. C. & Spangler, J. B. Emerging approaches for T cell-stimulating platform development. Cell Syst. 15, 1198–1208 (2024).

    Google Scholar 

14. Broaders, K. E., Cohen, J. A., Beaudette, T. T., Bachelder, E. M. & Fré Chet, J. M. J. Acetalated dextran is a chemically and biologically tunable material for particulate immunotherapy. Proc. Natl. Acad. Sci. USA 14, 5497–5502 (2009).

    Google Scholar 

15. Fontana, F. et al. Multistaged nanovaccines based on porous silicon@acetalated dextran@cancer cell membrane for cancer immunotherapy. Adv. Mater. 29, 1603239 (2017).

    Google Scholar 

16. Gao, H. et al. Comparative optimization of polysaccharide-based nanoformulations for cardiac RNAi therapy. Nat. Commun. 15, 5398 (2024).

    Google Scholar 

17. Cui, L., Cohen, J. A., Broaders, K. E., Beaudette, T. T. & Fréchet, J. M. J. Mannosylated dextran nanoparticles: A pH-sensitive system engineered for immunomodulation through mannose targeting. Bioconjug. Chem. 22, 949–957 (2011).

    Google Scholar 

18. Filippov, S. K. et al. Dynamic light scattering and transmission electron microscopy in drug delivery: a roadmap for correct characterization of nanoparticles and interpretation of results. Mater. Horiz. 10, 5354–5370 (2023).

    Google Scholar 

19. Kim, A., Ng, W. B., Bernt, W. & Cho, N. J. Validation of size estimation of nanoparticle tracking analysis on polydisperse macromolecule assembly. Sci Rep. 9, 2639 (2019).

20. Nanut, M. P., Sabotič, J., Jewett, A. & Kos, J. Cysteine cathepsins as regulators of the cytotoxicity of NK and T cells. Front. Immunol. 5, 616 (2014).

    Google Scholar 

21. Feng, B. et al. The type 2 cytokine Fc–IL-4 revitalizes exhausted CD8+ T cells against cancer. Nature 634, 712–720 (2024).

    Google Scholar 

22. Yamada-Hunter, S. A. et al. Engineered CD47 protects T cells for enhanced antitumour immunity. Nature 630, 457–465 (2024).

    Google Scholar 

23. Kalbasi, A. et al. Potentiating adoptive cell therapy using synthetic IL-9 receptors. Nature 607, 360–365 (2022).

    Google Scholar 

24. Zhang, A. Q. et al. Universal redirection of CAR T cells against solid tumours via membrane-inserted ligands for the CAR. Nat. Biomed. Eng. 7, 1113–1128 (2023).

    Google Scholar 

25. Zhang, D. K. Y. et al. Enhancing CAR-T cell functionality in a patient-specific manner. Nat. Commun. 14, 506 (2023).

    Google Scholar 

26. Otano, I. et al. CD137 (4-1BB) costimulation of CD8+ T cells is more potent when provided in cis than in trans with respect to CD3-TCR stimulation. Nat. Commun. 12, 7296 (2021).

    Google Scholar 

27. Wilson, T. L. et al. Common Trajectories of Highly Effective CD19-Specific CAR T Cells Identified by Endogenous T-cell Receptor Lineages. Cancer Discov. 12, 2098–2119 (2022).

    Google Scholar 

28. Li, X.-N. et al. XCL1-secreting CEA CAR-T cells enhance endogenous CD8 ⁺ T cell responses to tumor neoantigens to confer a long-term antitumor immunity. J. Immunother. Cancer 13, e010581 (2025).

    Google Scholar 

29. Roberts, E. W. et al. Critical Role for CD103+/CD141+ Dendritic Cells Bearing CCR7 for Tumor Antigen Trafficking and Priming of T Cell Immunity in Melanoma. Cancer Cell 30, 324–336 (2016).

    Google Scholar 

30. Qiao, J. & Fu, Y.-X. Cytokines that target immune killer cells against tumors. Cell Mol. Immunol. 17, 722–727 (2020).

    Google Scholar 

31. Foeng, J., Comerford, I. & McColl, S. R. Harnessing the chemokine system to home CAR-T cells into solid tumors. Cell Rep. Med 3, 100543 (2022).

    Google Scholar 

32. Luther, S. A. & Cyster, J. G. Chemokines as regulators of T cell differentiation. Nat. Immunol. 2, 102–107 (2001).

    Google Scholar 

33. Wauters, A. C. et al. Artificial antigen-presenting cell topology dictates T cell activation. ACS Nano 16, 15072–15085 (2022).

    Google Scholar 

34. Weller, S. et al. Influence of different conjugation methods for activating antibodies on polymeric nanoparticles: Effects for polyclonal expansion of human CD8+ T cells. Int Immunopharmacol. 129, 111643 (2024).

    Google Scholar 

35. Mateus, D. et al. Artificial Dendritic Cells: A New Era of Promising Antitumor Immunotherapy. Small 19, 2303940 (2023).

    Google Scholar 

36. Shen, D. T., Ma, J. S. Y., Mather, J., Vukmanovic, S. & Radoja, S. Activation of primary T lymphocytes results in lysosome development and polarized granule exocytosis in CD4+ and CD8+ subsets, whereas expression of lytic molecules confers cytotoxicity to CD8+ T cells. J. Leukoc. Biol. 80, 827–837 (2006).

    Google Scholar 

37. Hendriks, J. enny et al. CD27 is required for generation and long-term maintenance of T cell immunity. Nat. Immunol. 1, 433–440 (2000).

    Google Scholar 

38. Filosto, S. et al. Product Attributes of CAR T-cell Therapy Differentially Associate with Efficacy and Toxicity in Second-line Large B-cell Lymphoma (ZUMA-7). Blood Cancer Discov. 5, 21–33 (2024).

    Google Scholar 

39. Garfall, A. L. et al. T-cell phenotypes associated with effective CAR T-cell therapy in postinduction vs relapsed multiple myeloma. Blood Adv. 3, 2812–2815 (2019).

    Google Scholar 

40. Powell, D. J., Dudley, M. E., Robbins, P. F. & Rosenberg, S. A. Transition of late-stage effector T cells to CD27 CD28 tumor-reactive effector memory T cells in humans after adoptive cell transfer therapy. Blood 1, 241–250 (2005).

    Google Scholar 

41. Jaeger-Ruckstuhl, C. A. et al. Signaling via a CD27-TRAF2-SHP-1 axis during naive T cell activation promotes memory-associated gene regulatory networks. Immunity 57, 287–302 (2024).

    Google Scholar 

42. Bai, Z. et al. Single-cell CAR T atlas reveals type 2 function in 8-year leukaemia remission. Nature 634, 702–711 (2024).

    Google Scholar 

43. Zhao, Y. et al. IL-10-expressing CAR T cells resist dysfunction and mediate durable clearance of solid tumors and metastases. Nat. Biotechnol. 42, 1693–1704 (2024).

    Google Scholar 

44. Brudno, J. N. & Kochenderfer, J. N. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood 127, 3321–3330 (2016).

    Google Scholar 

45. Norelli, M. et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat. Med 24, 739–748 (2018).

    Google Scholar 

46. Giavridis, T. et al. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade letter. Nat. Med 24, 731–738 (2018).

    Google Scholar 

47. Dull, T. et al. A third-generation lentivirus vector with a conditional packaging system. J. Virol. 72, 8463–8471 (1998).

48. Guan, B., Wang, T. L. & Shih, I. M. ARID1A, a factor that promotes formation of SWI/SNF-mediated chromatin remodeling, is a tumor suppressor in gynecologic cancers. Cancer Res 71, 6718–6727 (2011).

    Google Scholar 

49. Bray, N. L., Pimentel, H., Melsted, P. & Pachter, L. Near-optimal probabilistic RNA-seq quantification. Nat. Biotechnol. 34, 525–527 (2016).

    Google Scholar 

50. Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

51. Gu, Z., Eils, R. & Schlesner, M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics 32, 2847–2849 (2016).

    Google Scholar 

52. Yu, G., Wang, L. G., Han, Y. & He, Q. Y. ClusterProfiler: An R package for comparing biological themes among gene clusters. OMICS 16, 284–287 (2012).

    Google Scholar 

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