Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy
Source abstract
Abstract
The tumour microenvironment thwarts conventional immunotherapy through multiple immunologic mechanisms, such as the secretion of the transforming growth factor-β (TGF-β), which stunts local tumour immune responses. Therefore, high doses of interleukin-2 (IL-2), a conventional cytokine for metastatic melanoma, induces only limited responses. To overcome the immunoinhibitory nature of the tumour microenvironment, we developed nanoscale liposomal polymeric gels (nanolipogels; nLGs) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers that can deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines in a sustained fashion to the tumour microenvironment. nLGs releasing TGF-β inhibitor and IL-2 significantly delayed tumour growth, increased survival of tumour-bearing mice, and increased the activity of natural killer cells and of intratumoral-activated CD8(+) T-cell infiltration. We demonstrate that the efficacy of nLGs in tumour immunotherapy results from a crucial mechanism involving activation of both innate and adaptive immune responses.
Source: europepmc · Quality: candidate unverified · Source record ↗
Research context
OpenAlex topics: Nanoplatforms for cancer theranostics · Immune cells in cancer · Nanoparticle-Based Drug Delivery
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
References (48)
Show source-provided references
1. Tawbi, H. A. & Kirkwood, J. M. Management of metastatic melanoma. Semin. Oncol. 34, 532–545 (2007).10.1053/j.seminoncol.2007.09.008 ↗
2. Atkins, M. B. et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: Analysis of 270 patients treated between 1985 and 1993. J. Clin. Oncol. 17, 2105–2116 (1999).10.1200/JCO.1999.17.7.2105 ↗
3. Acquavella, N. et al. Toxicity and activity of a twice daily high-dose bolus interleukin 2 regimen in patients with metastatic melanoma and metastatic renal cell cancer. J. Immunother. 31, 569–576 (2008).10.1097/CJI.0b013e318177a4ba ↗
4. Flavell, R. A., Sanjabi, S., Wrzesinski, S. H. & Licona-Limon, P. The polarization of immune cells in the tumour environment by TGFβ. Nature Rev. Immunol. 10, 554–567 (2010).10.1038/nri2808 ↗
5. Gorelik, L. & Flavell, R. A. Immune-mediated eradication of tumors through the blockade of transforming growth factor-β signaling in T cells. Nature Med. 7, 1118–1122 (2001).10.1038/nm1001-1118 ↗
6. Smyth, M. J. et al. CD4+CD25+ T regulatory cells suppress NK cell-mediated immunotherapy of cancer. J. Immunol. 176, 1582–1587 (2006).10.4049/jimmunol.176.3.1582 ↗
7. Wrzesinski, S. H., Wan, Y. Y. & Flavell, R. A. Transforming growth factor-β and the immune response: Implications for anticancer therapy. Clin. Cancer Res. 13, 5262–5270 (2007).10.1158/1078-0432.CCR-07-1157 ↗
8. Liu, V. C. et al. Tumor evasion of the immune system by converting CD4+CD25− T cells into CD4+CD25+ T regulatory cells: Role of tumor-derived TGF-β. J. Immunol. 178, 2883–2892 (2007).10.4049/jimmunol.178.5.2883 ↗
9. Fan, T. M., Kranz, D. M. & Roy, E. J. Enhancing antitumor immunity: combining IL-12 with TGF β1 antagonism. J. Immunother. 30, 479–489 (2007).10.1097/CJI.0b013e318031a2b2 ↗
10. Yingling, J. M., Blanchard, K. L. & Sawyer, J. S. Development of TGF-β signaling inhibitors for cancer therapy. Nature Rev. Drug. Disc. 3, 1011–1022 (2004).10.1038/nrd1580 ↗
11. Neville, M. E., Boni, L., Pflug, L., Popescu, M. C. & Robb, R. J. Biopharmaceutics of liposomal IL-2. Oncol. Cytok. 12, 1691–1701 (2000).
12. Feng, X-H. & Derynck, R. Specificity and versatility in TGF-β signaling through Smads. Annu. Rev. Cell Dev. Biol. 21, 659–693 (2005).10.1146/annurev.cellbio.21.022404.142018 ↗
13. Kano, M. R. et al. Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-β signaling. Proc. Natl Acad. Sci. USA 104, 3460–3465 (2007).10.1073/pnas.0611660104 ↗
14. Laouar, Y., Sutterwala, F. S., Gorelik, L. & Flavell, R. A. Transforming growth factor-beta control T helper type 1 cell development through regulation of natural killer interferon-gamma. Nature Immunol. 6, 600–607 (2005).10.1038/ni1197 ↗
15. Terabe, M. & Berzofsky, J. A. The role of NKT cells in tumor immunity. Adv. Cancer Res. 101, 277–348 (2008).10.1016/S0065-230X(08)00408-9 ↗
16. Gillies, S. D. et al. A low-toxicity IL-2-based immunocytokine retains antitumor activity despite its high degree of IL-2 receptor selectivity. Clin. Cancer Res. 17, 3673–3685 (2011).10.1158/1078-0432.CCR-10-2921 ↗
17. Teppler, H. et al. Prolonged immunostimulatory effect of low-dose polyethylene glycol interleukin 2 in patients with human immunodeficiency virus type 1 infection. J. Exp. Med. 177, 483–492 (1993).10.1084/jem.177.2.483 ↗
18. Letourneau, S. et al. IL-2/anti-IL-2 antibody complexes show strong biological activity by avoiding interaction with IL-2 receptor alpha subunit CD25. Proc. Natl Acad. Sci. USA 107, 2171–2176 (2010).10.1073/pnas.0909384107 ↗
19. Kaufman, H. L., Flanagan, K., Lee, C. S., Perretta, D. J. & Horig, H. Insertion of interleukin-2 (IL-2) and interleukin-12 (IL-12) genes into vaccinia virus results in effective anti-tumor responses without toxicity. Vaccine 20, 1862–1869 (2002).10.1016/S0264-410X(02)00032-4 ↗
20. Kanaoka, E. et al. A significant enhancement of therapeutic effect against hepatic metastases of M5076 in mice by a liposomal interleukin-2 (mixture). J. Control. Rel. 82, 183–187 (2002).10.1016/S0168-3659(02)00083-4 ↗
21. Neville, M. E., Robb, R. J. & Popescu, M. C. In situ vaccination against a non-immunogenic tumour using intratumoural injections of liposomal interleukin 2. Cytokine 16, 239–250 (2001).10.1006/cyto.2001.0963 ↗
22. Town, T. et al. Blocking TGF-β–Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nature Med. 14, 681–687 (2008).10.1038/nm1781 ↗
23. Byfield, S. D., Major, C., Laping, N. J. & Roberts, A. B. SB-505124 is a selective inhibitor of transforming growth factor-β type I receptors ALK4, ALK5, and ALK7. Mol. Pharm. 65, 744–752 (2004).10.1124/mol.65.3.744 ↗
24. Allen, T. M. & Martin, F. J. Advantages of liposomal delivery systems for anthracyclines. Semin. Oncol. 31, 5–15 (2004).10.1053/j.seminoncol.2004.08.001 ↗
25. Torchilin, V. P. Recent advances with liposomes as pharmaceutical carriers. Nature Rev. Drug. Disc. 4, 145–160 (2005).10.1038/nrd1632 ↗
26. Mundargi, R. C., Babu, V. R., Rangaswamy, V., Patel, P. & Aminabhavi, T. M. Nano/micro technologies for delivering macromolecular therapeutics using poly(D,L-lactide-co-glycolide) and its derivatives. J. Control Release 125, 193–209 (2008).10.1016/j.jconrel.2007.09.013 ↗
27. Thevenot, J., Troutier, A-L., David, L., Delair, T. & Ladavire, C. Steric stabilization of lipid/polymer particle assemblies by poly(ethylene glycol)-lipids. Biomacromole 8, 3651–3660 (2007).10.1021/bm700753q ↗
28. Moghimi, S. M. & Szebeni, J. Stealth liposomes and long circulating nanoparticles: Critical issues in pharmacokinetics, opsonization and protein-binding properties. Prog. Lipid Res. 42, 463–478 (2003).10.1016/S0163-7827(03)00033-X ↗
29. Moghimi, S. M., Hunter, A. C. & Murray, J. C. Long-circulating and target-specific nanoparticles: Theory to practice. Pharmacol. Rev. 53, 283–318 (2001).10.1016/S0031-6997(24)01494-7 ↗
30. Kazakov, S. & Levon, K. Liposome-nanogel structures for future pharmaceutical applications. Curr. Pharm Des. 12, 4713–4728 (2006).10.2174/138161206779026281 ↗
31. Meng, H. et al. Engineered design of mesoporous silica nanoparticles to deliver doxorubicin and P-glycoprotein siRNA to overcome drug resistance in a cancer cell line. ACS Nano 4, 4539–4550 (2010).10.1021/nn100690m ↗
32. Meng, H. et al. Autonomous in vitro anticancer drug release from mesoporous silica nanoparticles by pH-sensitive nanovalves. J. Am. Chem. Soc. 132, 12690–12697 (2010).10.1021/ja104501a ↗
33. Liong, M. et al. Multifunctional inorganic nanoparticles for imaging, targeting, and drug delivery. ACS Nano 2, 889–896 (2008).10.1021/nn800072t ↗
34. Ashley, C. E. et al. The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers. Nature Mater. 10, 389–397 (2011).10.1038/nmat2992 ↗
35. Sawhney, A. S., Pathak, C. P. & Hubbell, J. A. Bioerodible hydrogels based on photopolymerized poly(ethylene glycol)-co-poly(α-hydroxy acid) diacrylate macromers. Macromole 26, 581–587 (1993).10.1021/ma00056a005 ↗
36. Van Thienen, T. G., Raemdonck, K., Demeester, J. & De Smedt, S. C. Protein release from biodegradable dextran nanogels. Langmuir 23, 9794–9801 (2007).10.1021/la700736v ↗
37. Loftsson, T. & Duchene, D. Cyclodextrins and their pharmaceutical applications. Int. J. Pharm. 329, 1–11 (2007).10.1016/j.ijpharm.2006.10.044 ↗
38. Stella, J. & He, Q. Cyclodextrins. Toxicol. Pathol. 36, 30–42 (2008).10.1177/0192623307310945 ↗
39. Cote-Sierra, J. et al. Interleukin 2 plays a central role in Th2 differentiation. Proc. Natl Acad. Sci. USA 101, 3880–3885 (2004).10.1073/pnas.0400339101 ↗
40. Al-Soufi, W. et al. Fluorescence correlation spectroscopy, a tool to investigate supramolecular dynamics: inclusion complexes of pyronines with cyclodextrin. J. Am. Chem. Soc. 127, 8775–8784 (2005).10.1021/ja0508976 ↗
41. Wu, S. et al. Photoreversible fluorescence modulation of a rhodamine dye by supramolecular complexation with photosensitive cyclodextrin. Angew. Chem. Int. Ed. 46, 7015–7018 (2007).10.1002/anie.200701396 ↗
42. Farokhzad, O. C. et al. Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc. Natl Acad. Sci. USA 103, 6315–6320 (2006).10.1073/pnas.0601755103 ↗
43. Wischke, C. & Schwendeman, S. P. Principles of encapsulating hydrophobic drugs in PLA/PLGA microparticles. Int. J. Pharm. 364, 298–327 (2008).10.1016/j.ijpharm.2008.04.042 ↗
44. Van Elsas, A., Hurwitz, A. A. & Allison, J. P. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J. Exp. Med. 190, 355–366 (1999).10.1084/jem.190.3.355 ↗
45. Sanjabi, S., Mosaheb, M. M. & Flavell, R. A. Opposing effects of TGF-β and IL-15 cytokines control the number of short-lived effector CD8+ T cells. Immunity 31, 131–144 (2009).10.1016/j.immuni.2009.04.020 ↗
46. Hori, Y., Stern, P. J., Hynes, R. O. & Irvine, D. J. Engulfing tumors with synthetic extracellular matrices for cancer immunotherapy. Biomaterials 30, 6757–6767 (2009).10.1016/j.biomaterials.2009.08.037 ↗
47. Moon, J. J. et al. Interbilayer-crosslinked multilamellar vesicles as synthetic vaccines for potent humoral and cellular immune responses. Nature Mater. 10, 243–251 (2011).10.1038/nmat2960 ↗
48. Peer, D., Park, E. J., Morishita, Y., Carman, C. V. & Shimaoka, M. Systemic leukocyte-directed siRNA delivery revealing cyclin D1 as an anti-inflammatory target. Science 319, 627–630 (2008).10.1126/science.1149859 ↗