Overcoming biological barriers to improve solid tumor immunotherapy

Abstract

Cancer immunotherapy has been at the forefront of therapeutic interventions for many different tumor types over the last decade. While the discovery of immunotherapeutics continues to occur at an accelerated rate, their translation is often hindered by a lack of strategies to deliver them specifically into solid tumors. Accordingly, significant scientific efforts have been dedicated to understanding the underlying mechanisms that govern their delivery into tumors and the subsequent immune modulation. In this review, we aim to summarize the efforts focused on overcoming tumor-associated biological barriers and enhancing the potency of immunotherapy. We summarize the current understanding of biological barriers that limit the entry of intravascularly administered immunotherapies into the tumors, in vitro techniques developed to investigate the underlying transport processes, and delivery strategies developed to overcome the barriers. Overall, we aim to provide the reader with a framework that guides the rational development of technologies for improved solid tumor immunotherapy.

Graphical abstract

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References

  1. 1.

    Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy Science. 2013;342(6165):1432–3.

    CAS  PubMed  Google Scholar 

  2. 2.

    Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Finck A, Gill SI, June CH. Cancer immunotherapy comes of age and looks for maturity. Nat Commun. 2020;11(1):3325.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Markham MJ, Wachter K, Agarwal N, Bertagnolli MM, Chang SM, Dale W, et al. Clinical cancer advances 2020: annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol. 2020;38(10):1081.

    PubMed  Article  Google Scholar 

  5. 5.

    Myers JA, Miller JS. Exploring the NK cell platform for cancer immunotherapy. Nat Rev Clin Oncol. 2020.

  6. 6.

    Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol. 2020;20(11):651–68.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Burbage M, Amigorena S. A dendritic cell multitasks to tackle cancer. Nature. 2020;584(7822):533–4.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Robert C. A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun. 2020;11(1):3801.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Lawler SE, Speranza MC, Cho CF, Chiocca EA. Oncolytic viruses in cancer treatment: a review. JAMA Oncol. 2017;3(6):841–9.

    PubMed  Article  Google Scholar 

  10. 10.

    Riley RS, June CH, Langer R, Mitchell MJ. Delivery technologies for cancer immunotherapy. Nat Rev Drug Discov. 2019;18(3):175–96.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359(6382):1350–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Irvine DJ, Dane EL. Enhancing cancer immunotherapy with nanomedicine. Nat Rev Immunol. 2020;20(5):321–34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Sambi M, Bagheri L, Szewczuk MR. Current challenges in cancer immunotherapy: multimodal approaches to improve efficacy and patient response rates. J Oncol. 2019;2019:4508794.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. 14.

    Chouaib S, Lorens J. Editorial: Targeting the tumor microenvironment for a more effective and efficient cancer immunotherapy. Front Immunol. 2020;11:933.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Hegde PS, Chen DS. Top 10 challenges in cancer immunotherapy. Immunity. 2020;52(1):17–35.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Jain RK, Stylianopoulos T. Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol. 2010;7(11):653–64.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Mitragotri S, Burke PA, Langer R. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat Rev Drug Discov. 2014;13(9):655–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Zhao Z, Ukidve A, Krishnan V, Mitragotri S. Effect of physicochemical and surface properties on in vivo fate of drug nanocarriers. Adv Drug Deliv Rev. 2019;143:3–21.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Zhao Z, Ukidve A, Kim J, Mitragotri S. Targeting strategies for tissue-specific drug delivery. Cell. 2020;181(1):151–67.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol. 2015;33(9):941–51.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Singh B, Mitragotri S. Harnessing cells to deliver nanoparticle drugs to treat cancer. Biotechnol Adv. 2019.

  22. 22.

    Decuzzi P, Lee S, Bhushan B, Ferrari M. A theoretical model for the margination of particles within blood vessels. Ann Biomed Eng. 2005;33(2):179–90.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Shah S, Liu YL, Hu W, Gao JM. Modeling particle shape-dependent dynamics in nanomedicine. J Nanosci Nanotechnol. 2011;11(2):919–28.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Pyzik M, Sand KMK, Hubbard JJ, Andersen JT, Sandlie I, Blumberg RS. The neonatal Fc receptor (FcRn): a misnomer? Front Immunol. 2019;10:1540.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Di L. Strategic approaches to optimizing peptide ADME properties. Aaps J. 2015;17(1):134–43.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. 26.

    Juliano RL. The delivery of therapeutic oligonucleotides. Nucleic Acids Res. 2016;44(14):6518–48.

    PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Choi CHJ, Zuckerman JE, Webster P, Davis ME. Targeting kidney mesangium by nanoparticles of defined size. Proc Natl Acad Sci USA. 2011;108(16):6656–61.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Zuckerman JE, Choi CHJ, Han H, Davis ME. Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane. Proc Natl Acad Sci USA. 2012;109(8):3137–42.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Aggarwal P, Hall JB, McLeland CB, Dobrovolskaia MA, McNeil SE. Nanoparticle interaction with plasma proteins as it relates to particle biodistribution, biocompatibility and therapeutic efficacy. Adv Drug Deliver Rev. 2009;61(6):428–37.

    CAS  Article  Google Scholar 

  30. 30.

    Hoogenboezem EN, Duvall CL. Harnessing albumin as a carrier for cancer therapies. Adv Drug Deliv Rev. 2018;130:73–89.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Duan XP, Li YP. Physicochemical characteristics of nanoparticles affect circulation, biodistribution, cellular internalization, and trafficking. Small. 2013;9(9–10):1521–32.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Christian DA, Cai S, Garbuzenko OB, Harada T, Zajac AL, Minko T, et al. Flexible filaments for in vivo imaging and delivery: persistent circulation of filomicelles opens the dosage window for sustained tumor shrinkage. Mol Pharm. 2009;6(5):1343–52.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Decuzzi P, Godin B, Tanaka T, Lee SY, Chiappini C, Liu X, et al. Size and shape effects in the biodistribution of intravascularly injected particles. J Control Release. 2010;141(3):320–7.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Kinnear C, Moore TL, Rodriguez-Lorenzo L, Rothen-Rutishauser B, Petri-Fink A. Form follows function: nanoparticle shape and its implications for nanomedicine. Chem Rev. 2017;117(17):11476–521.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Docter D, Distler U, Storck W, Kuharev J, Wunsch D, Hahlbrock A, et al. Quantitative profiling of the protein coronas that form around nanoparticles. Nat Protoc. 2014;9(9):2030–44.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Arvizo RR, Miranda OR, Moyano DF, Walden CA, Giri K, Bhattacharya R, et al. Modulating pharmacokinetics, tumor uptake and biodistribution by engineered nanoparticles. PLoS One. 2011;6(9).

  37. 37.

    Gessner A, Lieske A, Paulke BR, Muller RH. Functional groups on polystyrene model nanoparticles: Influence on protein adsorption. J Biomed Mater Res A. 2003;65a(3):319–26.

  38. 38.

    Dufort S, Sancey L, Coll JL. Physico-chemical parameters that govern nanoparticles fate also dictate rules for their molecular evolution. Adv Drug Deliver Rev. 2012;64(2):179–89.

    CAS  Article  Google Scholar 

  39. 39.

    Xiao K, Li YP, Luo JT, Lee JS, Xiao WW, Gonik AM, et al. The effect of surface charge on in vivo biodistribution of PEG-oligocholic acid based micellar nanoparticles. Biomaterials. 2011;32(13):3435–46.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Champion JA, Mitragotri S. Role of target geometry in phagocytosis. Proc Natl Acad Sci USA. 2006;103(13):4930–4.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Champion JA, Mitragotri S. Shape induced inhibition of phagocytosis of polymer particles. Pharm Res. 2009;26(1):244–9.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer-chemotherapy - mechanism of tumoritropic accumulation of proteins and the antitumor agent Smancs. Can Res. 1986;46(12):6387–92.

    CAS  Google Scholar 

  43. 43.

    Maeda H, Nakamura H, Fang J. The EPR effect for macromolecular drug delivery to solid tumors: improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv Drug Deliver Rev. 2013;65(1):71–9.

    CAS  Article  Google Scholar 

  44. 44.

    Hoshyar N, Gray S, Han HB, Bao G. The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction. Nanomedicine. 2016;11(6):673–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Miao L, Huang L. Exploring the tumor microenvironment with nanoparticles. Cancer Treat Res. 2015;166:193–226.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Lee H, Shields AF, Siegel BA, Miller KD, Krop I, Ma CX, et al. (64)Cu-MM-302 positron emission tomography quantifies variability of enhanced permeability and retention of nanoparticles in relation to treatment response in patients with metastatic breast cancer. Clin Cancer Res. 2017;23(15):4190–202.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Sindhwani S, Syed AM, Ngai J, Kingston BR, Maiorino L, Rothschild J, et al. The entry of nanoparticles into solid tumours. Nat Mater. 2020;19(5):566–75.

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Welch JJ, Dean DA, Nilsson BL. Synthesis and application of peptide-siRNA nanoparticles from disulfide-constrained cyclic amphipathic peptides for the functional delivery of therapeutic oligonucleotides to the lung. Methods Mol Biol. 2021;2208:49–67.

    PubMed  Article  Google Scholar 

  49. 49.

    de Lazaro I, Mooney DJ. A nanoparticle’s pathway into tumours. Nat Mater. 2020;19(5):486–7.

    PubMed  Article  CAS  Google Scholar 

  50. 50.

    Martin JD, Seano G, Jain RK. Normalizing function of tumor vessels: progress, opportunities, and challenges. Annu Rev Physiol. 2019;81:505–34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Costa A, Kieffer Y, Scholer-Dahirel A, Pelon F, Bourachot B, Cardon M, et al. Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer. Cancer Cell. 2018;33(3):463–79 e10.

  52. 52.

    Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018;15(5):325–40.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Stylianopoulos T, Munn LL, Jain RK. Reengineering the physical microenvironment of tumors to improve drug delivery and efficacy: from mathematical modeling to bench to bedside. Trends Cancer. 2018;4(4):292–319.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Stylianopoulos T, Martin JD, Chauhan VP, Jain SR, Diop-Frimpong B, Bardeesy N, et al. Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors. Proc Natl Acad Sci USA. 2012;109(38):15101–8.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Jain RK, Martin JD, Stylianopoulos T. The role of mechanical forces in tumor growth and therapy. Annu Rev Biomed Eng. 2014;16:321–46.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Kalli M, Stylianopoulos T. Defining the role of solid stress and matrix stiffness in cancer cell proliferation and metastasis. Front Oncol. 2018;8:55.

    PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Stylianopoulos T. The solid mechanics of cancer and strategies for improved therapy. J Biomech Eng. 2017;139(2).

  58. 58.

    Mok W, Boucher Y, Jain RK. Matrix metalloproteinases-1 and -8 improve the distribution and efficacy of an oncolytic virus. Cancer Res. 2007;67(22):10664–8.

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Sherman MH, Yu RT, Engle DD, Ding N, Atkins AR, Tiriac H, et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell. 2014;159(1):80–93.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Black KC, Wang Y, Luehmann HP, Cai X, Xing W, Pang B, et al. Radioactive 198Au-doped nanostructures with different shapes for in vivo analyses of their biodistribution, tumor uptake, and intratumoral distribution. ACS Nano. 2014;8(5):4385–94.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Gratton SEA, Ropp PA, Pohlhaus PD, Luft JC, Madden VJ, Napier ME, et al. The effect of particle design on cellular internalization pathways. Proc Natl Acad Sci USA. 2008;105(33):11613–8.

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Wasungu L, Hoekstra D. Cationic lipids, lipoplexes and intracellular delivery of genes. J Control Release. 2006;116(2):255–64.

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Chou LYT, Ming K, Chan WCW. Strategies for the intracellular delivery of nanoparticles. Chem Soc Rev. 2011;40(1):233–45.

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Kumar V, Qin J, Jiang Y, Duncan RG, Brigham B, Fishman S, et al. Shielding of lipid nanoparticles for siRNA delivery: impact on physicochemical properties, cytokine induction, and efficacy. Mol Ther Nucleic Acids. 2014;3:e210.

    PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Bolhassani A. Potential efficacy of cell-penetrating peptides for nucleic acid and drug delivery in cancer. Biochim Biophys Acta. 2011;1816(2):232–46.

    CAS  PubMed  Google Scholar 

  66. 66.

    Jain RK. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell. 2014;26(5):605–22.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Yan Y, Ding H. pH-responsive nanoparticles for cancer immunotherapy: a brief review. Nanomaterials (Basel). 2020;10(8).

  68. 68.

    Evans MA, Huang PJ, Iwamoto Y, Ibsen KN, Chan EM, Hitomi Y, et al. Macrophage-mediated delivery of light activated nitric oxide prodrugs with spatial, temporal and concentration control. Chem Sci. 2018;9(15):3729–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Duan Q, Zhang H, Zheng J, Zhang L. Turning cold into hot: firing up the tumor microenvironment. Trends Cancer. 2020;6(7):605–18.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Labani-Motlagh A, Ashja-Mahdavi M, Loskog A. The tumor microenvironment: a milieu hindering and obstructing antitumor immune responses. Front Immunol. 2020;11:940.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    O’Donnell JS, Teng MWL, Smyth MJ. Cancer immunoediting and resistance to T cell-based immunotherapy. Nat Rev Clin Oncol. 2019;16(3):151–67.

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Nagarsheth N, Wicha MS, Zou WP. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol. 2017;17(9):559–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1–10.

    PubMed  Article  CAS  Google Scholar 

  74. 74.

    Martin JD, Cabral H, Stylianopoulos T, Jain RK. Improving cancer immunotherapy using nanomedicines: progress, opportunities and challenges. Nat Rev Clin Oncol. 2020;17(4):251–66.

    PubMed  Article  Google Scholar 

  75. 75.

    Soliman HH. nab-Paclitaxel as a potential partner with checkpoint inhibitors in solid tumors. Onco Targets Ther. 2017;10:101–12.

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Min Y, Roche KC, Tian S, Eblan MJ, McKinnon KP, Caster JM, et al. Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy. Nat Nanotechnol. 2017;12(9):877–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Smith AAA, Gale EC, Roth GA, Maikawa CL, Correa S, Yu AC, et al. Nanoparticles presenting potent TLR7/8 agonists enhance anti-PD-L1 immunotherapy in cancer treatment. Biomacromol. 2020;21(9):3704–12.

    CAS  Article  Google Scholar 

  78. 78.

    Nuhn L, De Koker S, Van Lint S, Zhong Z, Catani JP, Combes F, et al. Nanoparticle-conjugate TLR7/8 agonist localized immunotherapy provokes safe antitumoral responses. Adv Mater. 2018;30(45):e1803397.

    PubMed  Article  CAS  Google Scholar 

  79. 79.

    Ishihara J, Ishihara A, Sasaki K, Lee SS, Williford JM, Yasui M, et al. Targeted antibody and cytokine cancer immunotherapies through collagen affinity. Sci Transl Med. 2019;11(487).

  80. 80.

    Ellis PM, Vella ET, Ung YC. Immune checkpoint inhibitors for patients with advanced non-small-cell lung cancer: a systematic review. Clin Lung Cancer. 2017;18(5):444–59 e1.

  81. 81.

    Pao W, Ooi CH, Birzele F, Ruefli-Brasse A, Cannarile MA, Reis B, et al. Tissue-specific immunoregulation: a call for better understanding of the “immunostat” in the context of cancer. Cancer Discov. 2018;8(4):395–402.

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Cheon D-J, Orsulic S. Mouse models of cancer. Annu Rev Pathol. 2011;6:95–119.

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Lwin TM, Hoffman RM, Bouvet M. Advantages of patient-derived orthotopic mouse models and genetic reporters for developing fluorescence-guided surgery. J Surg Oncol. 2018;118(2):253–64.

    PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Perrin S. Preclinical research: make mouse studies work. Nature News. 2014;507(7493):423.

    Article  Google Scholar 

  85. 85.

    Fogh J, Fogh JM, Orfeo T. One hundred and twenty-seven cultured human tumor cell lines producing tumors in nude mice. J Natl Cancer Inst. 1977;59(1):221–6.

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Garber K. From human to mouse and back:“tumorgraft” models surge in popularity. Oxford University Press; 2009.

  87. 87.

    Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci. 2013;110(9):3507–12.

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Tentler JJ, Tan AC, Weekes CD, Jimeno A, Leong S, Pitts TM, et al. Patient-derived tumour xenografts as models for oncology drug development. Nature reviews Clinical oncology. 2012;9(6):338–50.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Aparicio S, Hidalgo M, Kung AL. Examining the utility of patient-derived xenograft mouse models. Nat Rev Cancer. 2015;15(5):311–6.

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Kalscheuer H, Danzl N, Onoe T, Faust T, Winchester R, Goland R, et al. A model for personalized in vivo analysis of human immune responsiveness. Sci Transl Med. 2012;4(125):125ra30-ra30.

  91. 91.

    Pijuan J, Barcelo C, Moreno DF, Maiques O, Siso P, Marti RM, et al. In vitro cell migration, invasion, and adhesion assays: from cell imaging to data analysis. Front Cell Dev Biol. 2019;7:107.

    PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Cerottini JC, Nordin AA, Brunner KT. Specific in vitro cytotoxicity of thymus-derived lymphocytes sensitized to alloantigens. Nature. 1970;228(5278):1308–9.

    CAS  PubMed  Article  Google Scholar 

  93. 93.

    Clay TM, Hobeika AC, Mosca PJ, Lyerly HK, Morse MA. Assays for monitoring cellular immune responses to active immunotherapy of cancer. Clin Cancer Res. 2001;7(5):1127–35.

    CAS  PubMed  Google Scholar 

  94. 94.

    Cerignoli F, Abassi YA, Lamarche BJ, Guenther G, Santa Ana D, Guimet D, et al. In vitro immunotherapy potency assays using real-time cell analysis. PLoS One. 2018;13(3):e0193498.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  95. 95.

    Newell EW, Sigal N, Nair N, Kidd BA, Greenberg HB, Davis MM. Combinatorial tetramer staining and mass cytometry analysis facilitate T-cell epitope mapping and characterization. Nat Biotechnol. 2013;31(7):623–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Dolton G, Tungatt K, Lloyd A, Bianchi V, Theaker SM, Trimby A, et al. More tricks with tetramers: a practical guide to staining T cells with peptide-MHC multimers. Immunology. 2015;146(1):11–22.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    Burleson GR, Burleson FG, Dietert RR. The cytotoxic T lymphocyte assay for evaluating cell-mediated immune function. Methods Mol Biol. 2010;598:195–205.

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Zaritskaya L, Shurin MR, Sayers TJ, Malyguine AM. New flow cytometric assays for monitoring cell-mediated cytotoxicity. Expert Rev Vaccines. 2010;9(6):601–16.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Lovelace P, Maecker HT. Multiparameter intracellular cytokine staining. Methods Mol Biol. 2018;1678:151–66.

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Schmidt H, Sorensen BS, von der Maase H, Bang C, Agger R, Hokland M, et al. Quantitative RT-PCR assessment of melanoma cells in peripheral blood during immunotherapy for metastatic melanoma. Melanoma Res. 2002;12(6):585–92.

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    van Vloten JP, Santry LA, McAusland TM, Karimi K, McFadden G, Petrik JJ, et al. Quantifying antigen-specific T cell responses when using antigen-agnostic immunotherapies. Mol Ther Methods Clin Dev. 2019;13:154–66.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  102. 102.

    Ritch SJ, Brandhagen BN, Goyeneche AA, Telleria CM. Advanced assessment of migration and invasion of cancer cells in response to mifepristone therapy using double fluorescence cytochemical labeling. BMC Cancer. 2019;19(1):376.

    PubMed  PubMed Central  Article  Google Scholar 

  103. 103.

    Leconet W, Larbouret C, Chardes T, Thomas G, Neiveyans M, Busson M, et al. Preclinical validation of AXL receptor as a target for antibody-based pancreatic cancer immunotherapy. Oncogene. 2014;33(47):5405–14.

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Conde J, Oliva N, Atilano M, Song HS, Artzi N. Self-assembled RNA-triple-helix hydrogel scaffold for microRNA modulation in the tumour microenvironment. Nat Mater. 2016;15(3):353–63.

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Muliaditan T, Caron J, Okesola M, Opzoomer JW, Kosti P, Georgouli M, et al. Macrophages are exploited from an innate wound healing response to facilitate cancer metastasis. Nat Commun. 2018;9(1):2951.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  106. 106.

    Hao X, Li C, Zhang Y, Wang H, Chen G, Wang M, et al. Programmable chemotherapy and immunotherapy against breast cancer guided by multiplexed fluorescence imaging in the second near-infrared window. Adv Mater. 2018;30(51):e1804437.

    PubMed  Article  CAS  Google Scholar 

  107. 107.

    Sherman H, Gitschier HJ, Rossi AE. A novel three-dimensional immune oncology model for high-throughput testing of tumoricidal activity. Front Immunol. 2018a;9:857.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  108. 108.

    Hoogduijn MJ, Popp F, Verbeek R, Masoodi M, Nicolaou A, Baan C, et al. The immunomodulatory properties of mesenchymal stem cells and their use for immunotherapy. Int Immunopharmacol. 2010;10(12):1496–500.

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Leclerc M, Voilin E, Gros G, Corgnac S, de Montpreville V, Validire P, et al. Regulation of antitumour CD8 T-cell immunity and checkpoint blockade immunotherapy by Neuropilin-1. Nat Commun. 2019;10(1):3345.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  110. 110.

    Weiswald LB, Bellet D, Dangles-Marie V. Spherical cancer models in tumor biology. Neoplasia. 2015;17(1):1–15.

    PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Nath S, Devi GR. Three-dimensional culture systems in cancer research: Focus on tumor spheroid model. Pharmacol Ther. 2016;163:94–108.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Kim J, Li WA, Choi Y, Lewin SA, Verbeke CS, Dranoff G, et al. Injectable, spontaneously assembling, inorganic scaffolds modulate immune cells in vivo and increase vaccine efficacy. Nat Biotechnol. 2015;33(1):64–72.

    CAS  PubMed  Article  Google Scholar 

  113. 113.

    Friedrich J, Ebner R, Kunz-Schughart LA. Experimental anti-tumor therapy in 3-D: spheroids–old hat or new challenge? Int J Radiat Biol. 2007;83(11–12):849–71.

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Kelm JM, Timmins NE, Brown CJ, Fussenegger M, Nielsen LK. Method for generation of homogeneous multicellular tumor spheroids applicable to a wide variety of cell types. Biotechnol Bioeng. 2003;83(2):173–80.

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Friedrich J, Seidel C, Ebner R, Kunz-Schughart LA. Spheroid-based drug screen: considerations and practical approach. Nat Protoc. 2009;4(3):309.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  116. 116.

    Sherman H, Gitschier HJ, Rossi AE. A novel three-dimensional immune oncology model for high-throughput testing of tumoricidal activity. Front Immunol. 2018;9:857.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  117. 117.

    Zhou S, Zhu M, Meng F, Shao J, Xu Q, Wei J, et al. Evaluation of PD-1 blockade using a multicellular tumor spheroid model. Am J Transl Res. 2019;11(12):7471.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D, et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 2005;65(13):5506–11.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  119. 119.

    Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F, et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell. 2007;1(4):389–402.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  120. 120.

    Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 2008;15(3):504–14.

    CAS  PubMed  Article  Google Scholar 

  121. 121.

    Yu M, Bardia A, Aceto N, Bersani F, Madden MW, Donaldson MC, et al. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. science. 2014;345(6193):216–20.

  122. 122.

    Smart CE, Morrison BJ, Saunus JM, Vargas AC, Keith P, Reid L, et al. In vitro analysis of breast cancer cell line tumourspheres and primary human breast epithelia mammospheres demonstrates inter-and intrasphere heterogeneity. PLoS One. 2013;8(6):e64388.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Chandrasekaran S, Marshall JR, Messing JA, Hsu JW, King MR. TRAIL-mediated apoptosis in breast cancer cells cultured as 3D spheroids. PLoS One. 2014;9(10):e111487.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  124. 124.

    Snyder KA, Hughes MR, Hedberg B, Brandon J, Hernaez DC, Bergqvist P, et al. Podocalyxin enhances breast tumor growth and metastasis and is a target for monoclonal antibody therapy. Breast Cancer Res. 2015;17(1):1–14.

    CAS  Article  Google Scholar 

  125. 125.

    Wang B, Wang Q, Wang Z, Jiang J, Yu SC, Ping YF, et al. Metastatic consequences of immune escape from NK cell cytotoxicity by human breast cancer stem cells. Can Res. 2014;74(20):5746–57.

    CAS  Article  Google Scholar 

  126. 126.

    Kajihara M, Takakura K, Kanai T, Ito Z, Saito K, Takami S, et al. Dendritic cell-based cancer immunotherapy for colorectal cancer. World J Gastroenterol. 2016;22(17):4275.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. 127.

    Koido S, Ohkusa T, Homma S, Namiki Y, Takakura K, Saito K, et al. Immunotherapy for colorectal cancer. World J Gastroenterol: WJG. 2013;19(46):8531.

    CAS  PubMed  Article  Google Scholar 

  128. 128.

    Qureshi-Baig K, Ullmann P, Rodriguez F, Frasquilho S, Nazarov PV, Haan S, et al. What do we learn from spheroid culture systems? Insights from tumorspheres derived from primary colon cancer tissue. PLoS One. 2016;11(1):e0146052.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  129. 129.

    Endo H, Okami J, Okuyama H, Kumagai T, Uchida J, Kondo J, et al. Spheroid culture of primary lung cancer cells with neuregulin 1/HER3 pathway activation. J Thorac Oncol. 2013;8(2):131–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  130. 130.

    Xu C, Fillmore CM, Koyama S, Wu H, Zhao Y, Chen Z, et al. Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell. 2014;25(5):590–604.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 131.

    Jachetti E, Caputo S, Mazzoleni S, Brambillasca CS, Parigi SM, Grioni M, et al. Tenascin-C protects cancer stem–like cells from immune surveillance by arresting T-cell activation. Can Res. 2015;75(10):2095–108.

    CAS  Article  Google Scholar 

  132. 132.

    Xu Q, Liu G, Yuan X, Xu M, Wang H, Ji J, et al. Antigen-specific T-cell response from dendritic cell vaccination using cancer stem-like cell-associated antigens. Stem Cells. 2009;27(8):1734–40.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    Schatton T, Frank MH. Antitumor immunity and cancer stem cells. Ann N Y Acad Sci. 2009;1176:154.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445(7123):111–5.

    CAS  PubMed  Article  Google Scholar 

  135. 135.

    Szaryńska M, Olejniczak A, Kobiela J, Łaski D, Śledziński Z, Kmieć Z. Cancer stem cells as targets for DC-based immunotherapy of colorectal cancer. Sci Rep. 2018;8(1):1–22.

    Article  CAS  Google Scholar 

  136. 136.

    Weiswald L, Richon S, Validire P, Briffod M, Lai-Kuen R, Cordelieres F, et al. Newly characterised ex vivo colospheres as a three-dimensional colon cancer cell model of tumour aggressiveness. Br J Cancer. 2009;101(3):473–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. 137.

    Weiswald L, Richon S, Massonnet G, Guinebretiere J, Vacher S, Laurendeau I, et al. A short-term colorectal cancer sphere culture as a relevant tool for human cancer biology investigation. Br J Cancer. 2013;108(8):1720–31.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. 138.

    Kondo J, Endo H, Okuyama H, Ishikawa O, Iishi H, Tsujii M, et al. Retaining cell–cell contact enables preparation and culture of spheroids composed of pure primary cancer cells from colorectal cancer. Proc Natl Acad Sci. 2011;108(15):6235–40.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  139. 139.

    Young SR, Saar M, Santos J, Nguyen HM, Vessella RL, Peehl DM. Establishment and serial passage of cell cultures derived from LuCaP xenografts. Prostate. 2013;73(12):1251–62.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. 140.

    Rajcevic U, Knol JC, Piersma S, Bougnaud S, Fack F, Sundlisaeter E, et al. Colorectal cancer derived organotypic spheroids maintain essential tissue characteristics but adapt their metabolism in culture. Proteome Science. 2014;12(1):39.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  141. 141.

    Bjerkvig R. Spheroid Culture in Cancer Research (1991): CRC press; 2017.

  142. 142.

    Sundlisæter E, Wang J, Sakariassen P, Marie M, Mathisen J, Karlsen B, et al. Primary glioma spheroids maintain tumourogenicity and essential phenotypic traits after cryopreservation. Neuropathol Appl Neurobiol. 2006;32(4):419–27.

    PubMed  Article  PubMed Central  Google Scholar 

  143. 143.

    Kong JCH, Guerra GR, Millen RM, Roth S, Xu H, Neeson PJ, et al. Tumor-infiltrating lymphocyte function predicts response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. JCO Precis Oncol. 2018;2:1–15.

    Google Scholar 

  144. 144.

    Park D, Son K, Hwang Y, Ko J, Lee Y, Doh J, et al. High-throughput microfluidic 3D cytotoxicity assay for cancer immunotherapy (CACI-IMPACT platform). Front Immunol. 2019;10:1133.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. 145.

    Kim S, Kim HJ, Jeon NL. Biological applications of microfluidic gradient devices. Integr Biol. 2010;2(11–12):584–603.

    CAS  Article  Google Scholar 

  146. 146.

    Van Duinen V, Trietsch SJ, Joore J, Vulto P, Hankemeier T. Microfluidic 3D cell culture: from tools to tissue models. Curr Opin Biotechnol. 2015;35:118–26.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  147. 147.

    Zhao Z, McGill J, Gamero-Kubota P, He M. Microfluidic on-demand engineering of exosomes towards cancer immunotherapy. Lab Chip. 2019;19(10):1877–86.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. 148.

    Taghikhani A, Farzaneh F, Sharifzad F, Mardpour S, Ebrahimi M. Hassan ZM. Engineered Tumor-Derived Extracellular Vesicles: Potentials in Cancer Immunotherapy. Front Immunol; 2020. p. 11.

    Google Scholar 

  149. 149.

    Wan Z, Gao X, Dong Y, Zhao Y, Chen X, Yang G, et al. Exosome-mediated cell-cell communication in tumor progression. Am J Cancer Res. 2018;8(9):1661.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Yu X, Harris SL, Levine AJ. The regulation of exosome secretion: a novel function of the p53 protein. Can Res. 2006;66(9):4795–801.

    CAS  Article  Google Scholar 

  151. 151.

    Ning Y, Shen K, Wu Q, Sun X, Bai Y, Xie Y, et al. Tumor exosomes block dendritic cells maturation to decrease the T cell immune response. Immunol Lett. 2018;199:36–43.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  152. 152.

    Andre F, Schartz NE, Movassagh M, Flament C, Pautier P, Morice P, et al. Malignant effusions and immunogenic tumour-derived exosomes. The Lancet. 2002;360(9329):295–305.

    CAS  Article  Google Scholar 

  153. 153.

    Robbins PD, Morelli AE. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol. 2014;14(3):195–208.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. 154.

    Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell derived exosomes. Nat Med. 1998;4(5):594–600.

    CAS  PubMed  Article  Google Scholar 

  155. 155.

    Wolfers J, Lozier A, Raposo G, Regnault A, Théry C, Masurier C, et al. Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat Med. 2001;7(3):297–303.

    CAS  PubMed  Article  Google Scholar 

  156. 156.

    Caradec J, Kharmate G, Hosseini-Beheshti E, Adomat H, Gleave M, Guns E. Reproducibility and efficiency of serum-derived exosome extraction methods. Clin Biochem. 2014;47(13–14):1286–92.

    CAS  PubMed  Article  Google Scholar 

  157. 157.

    Mol EA, Goumans M-J, Doevendans PA, Sluijter JP, Vader P. Higher functionality of extracellular vesicles isolated using size-exclusion chromatography compared to ultracentrifugation. Nanomed: Nanotechnol, Biol Med. 2017;13(6):2061–5.

  158. 158.

    Witwer KW, Buzás EI, Bemis LT, Bora A, Lässer C, Lötvall J, et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. Journal of extracellular vesicles. 2013;2(1):20360.

    Article  CAS  Google Scholar 

  159. 159.

    Tauro BJ, Greening DW, Mathias RA, Ji H, Mathivanan S, Scott AM, et al. Comparison of ultracentrifugation, density gradient separation, and immunoaffinity capture methods for isolating human colon cancer cell line LIM1863-derived exosomes. Methods. 2012;56(2):293–304.

    CAS  PubMed  Article  Google Scholar 

  160. 160.

    Parlato S, De Ninno A, Molfetta R, Toschi E, Salerno D, Mencattini A, et al. 3D Microfluidic model for evaluating immunotherapy efficacy by tracking dendritic cell behaviour toward tumor cells. Sci Rep. 2017;7(1):1–16.

    Article  Google Scholar 

  161. 161.

    Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer. 2008;8(4):299–308.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. 162.

    Ma S, Li X, Wang X, Cheng L, Li Z, Zhang C, et al. Current progress in CAR-T cell therapy for solid tumors. Int J Biol Sci. 2019;15(12):2548–60.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. 163.

    Schmidts A, Maus MV. Making CAR T cells a solid option for solid tumors. Front Immunol. 2018;9:2593.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  164. 164.

    Slaney CY, Kershaw MH, Darcy PK. Trafficking of T cells into tumors. Can Res. 2014;74(24):7168.

    CAS  Article  Google Scholar 

  165. 165.

    Tormoen GW, Crittenden MR, Gough MJ. Role of the immunosuppressive microenvironment in immunotherapy. Adv Radiat Oncol. 2018;3(4):520–6.

    PubMed  PubMed Central  Article  Google Scholar 

  166. 166.

    Fousek K, Ahmed N. The evolution of T-cell therapies for solid malignancies. Clin Cancer Res. 2015;21(15):3384–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  167. 167.

    Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies. Nat Rev Clin Oncol. 2018;15(2):81–94.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  168. 168.

    Wei J, Han X, Bo J, Han W. Target selection for CAR-T therapy. J Hematol Oncol. 2019;12(1):62.

    PubMed  PubMed Central  Article  Google Scholar 

  169. 169.

    Zhang Z, Jiang D, Yang H, He Z, Liu X, Qin W, et al. Modified CAR T cells targeting membrane-proximal epitope of mesothelin enhances the antitumor function against large solid tumor. Cell Death Dis. 2019;10(7):476.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  170. 170.

    Lv J, Zhao R, Wu D, Zheng D, Wu Z, Shi J, et al. Mesothelin is a target of chimeric antigen receptor T cells for treating gastric cancer. J Hematol Oncol. 2019;12(1):18.

    PubMed  PubMed Central  Article  Google Scholar 

  171. 171.

    Morello A, Sadelain M, Adusumilli PS. Mesothelin-targeted CARs: driving T cells to solid tumors. Cancer Discov. 2016;6(2):133–46.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  172. 172.

    Koneru M, Purdon TJ, Spriggs D, Koneru S, Brentjens RJ. IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. Oncoimmunology. 2015;4(3):e994446.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  173. 173.

    Wang W, Ma Y, Li J, Shi HS, Wang LQ, Guo FC, et al. Specificity redirection by CAR with human VEGFR-1 affinity endows T lymphocytes with tumor-killing ability and anti-angiogenic potency. Gene Ther. 2013;20(10):970–8.

    CAS  PubMed  Article  Google Scholar 

  174. 174.

    Lanitis E, Irving M, Coukos G. Targeting the tumor vasculature to enhance T cell activity. Curr Opin Immunol. 2015;33:55–63.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  175. 175.

    Bocca P, Di Carlo E, Caruana I, Emionite L, Cilli M, De Angelis B, et al. Bevacizumab-mediated tumor vasculature remodelling improves tumor infiltration and antitumor efficacy of GD2-CAR T cells in a human neuroblastoma preclinical model. Oncoimmunology. 2018;7(1):e1378843.

    Article  Google Scholar 

  176. 176.

    Panni RZ, Linehan DC, DeNardo DG. Targeting tumor-infiltrating macrophages to combat cancer. Immunotherapy. 2013;5(10):1075–87.

    CAS  PubMed  Article  Google Scholar 

  177. 177.

    Lee S, Kivimäe S, Dolor A, Szoka FC. Macrophage-based cell therapies: the long and winding road. J Control Release. 2016;240:527–40.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  178. 178.

    Klichinsky M, Ruella M, Shestova O, Lu XM, Best A, Zeeman M, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol. 2020;38(8):947–53.

    CAS  PubMed  Article  Google Scholar 

  179. 179.

    Suck G, Odendahl M, Nowakowska P, Seidl C, Wels WS, Klingemann HG, et al. NK-92: an ‘off-the-shelf therapeutic’ for adoptive natural killer cell-based cancer immunotherapy. Cancer Immunol Immunother. 2016;65(4):485–92.

    CAS  PubMed  Article  Google Scholar 

  180. 180.

    Zhang C, Oberoi P, Oelsner S, Waldmann A, Lindner A, Tonn T, et al. Chimeric antigen receptor-engineered NK-92 cells: an off-the-shelf cellular therapeutic for targeted elimination of cancer cells and induction of protective antitumor immunity. Front Immunol. 2017;8:533.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  181. 181.

    Parihar R, Rivas C, Huynh M, Omer B, Lapteva N, Metelitsa LS, et al. NK cells expressing a chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors. Cancer Immunol Res. 2019;7(3):363.

    CAS  PubMed  Article  Google Scholar 

  182. 182.

    Han J, Chu J, Keung Chan W, Zhang J, Wang Y, Cohen JB, et al. CAR-engineered nk cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. Sci Rep. 2015;5(1):11483.

    PubMed  PubMed Central  Article  Google Scholar 

  183. 183.

    Chu DT, Nguyen TT, Tien NLB, Tran DK, Jeong JH, Anh PG, et al. Recent progress of stem cell therapy in cancer treatment: molecular mechanisms and potential applications. Cells. 2020;9(3).

  184. 184.

    Gschweng E, De Oliveira S, Kohn DB. Hematopoietic stem cells for cancer immunotherapy. Immunol Rev. 2014;257(1):237–49.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  185. 185.

    Xie C, Yang Z, Suo Y, Chen Q, Wei D, Weng X, et al. Systemically infused mesenchymal stem cells show different homing profiles in healthy and tumor mouse models. Stem Cells Transl Med. 2017;6(4):1120–31.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  186. 186.

    Mooney R, Hammad M, Batalla-Covello J, Abdul Majid A, Aboody KS. Concise review: Neural stem cell-mediated targeted cancer therapies. Stem Cells Transl Med. 2018;7(10):740–7.

    PubMed  PubMed Central  Article  Google Scholar 

  187. 187.

    Shah K. Mesenchymal stem cells engineered for cancer therapy. Adv Drug Deliv Rev. 2012;64(8):739–48.

    CAS  PubMed  Article  Google Scholar 

  188. 188.

    Chulpanova DS, Kitaeva KV, Tazetdinova LG, James V, Rizvanov AA, Solovyeva VV. Application of mesenchymal stem cells for therapeutic agent delivery in anti-tumor treatment. Front Pharmacol. 2018;9:259.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  189. 189.

    Bago JR, Sheets KT, Hingtgen SD. Neural stem cell therapy for cancer. Methods. 2016;99:37–43.

    CAS  PubMed  Article  Google Scholar 

  190. 190.

    Dührsen L, Hartfuß S, Hirsch D, Geiger S, Maire CL, Sedlacik J, et al. Preclinical analysis of human mesenchymal stem cells: tumor tropism and therapeutic efficiency of local HSV-TK suicide gene therapy in glioblastoma. Oncotarget. 2019;10(58).

  191. 191.

    Belderbos RA, Aerts JGJV, Vroman H. Enhancing dendritic cell therapy in solid tumors with immunomodulating conventional treatment. Molecular Therapy - Oncolytics. 2019;13:67–81.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  192. 192.

    Shao K, Singha S, Clemente-Casares X, Tsai S, Yang Y, Santamaria P. Nanoparticle-based immunotherapy for cancer. ACS Nano. 2015;9(1):16–30.

    CAS  PubMed  Article  Google Scholar 

  193. 193.

    Shields CW IV, Wang LLW, Evans MA, Mitragotri S. Materials for Immunotherapy. Adv Mater. 2020;32(13):1901633.

    CAS  Article  Google Scholar 

  194. 194.

    Wilhelm S, Tavares AJ, Dai Q, Ohta S, Audet J, Dvorak HF, et al. Analysis of nanoparticle delivery to tumours. Nat Rev Mater. 2016;1(5).

  195. 195.

    Mitchell MJ, Wayne E, Rana K, Schaffer CB, King MR. TRAIL-coated leukocytes that kill cancer cells in the circulation. Proc Natl Acad Sci USA. 2014;111(3):930–5.

    CAS  PubMed  Article  Google Scholar 

  196. 196.

    Wayne EC, Chandrasekaran S, Mitchell MJ, Chan MF, Lee RE, Schaffer CB, et al. TRAIL-coated leukocytes that prevent the bloodborne metastasis of prostate cancer. J Control Release. 2016;223:215–23.

    CAS  PubMed  Article  Google Scholar 

  197. 197.

    Rosalia RA, Cruz LJ, van Duikeren S, Tromp AT, Silva AL, Jiskoot W, et al. CD40-targeted dendritic cell delivery of PLGA-nanoparticle vaccines induce potent anti-tumor responses. Biomaterials. 2015;40:88–97.

    CAS  PubMed  Article  Google Scholar 

  198. 198.

    Buss CG, Bhatia SN. Nanoparticle delivery of immunostimulatory oligonucleotides enhances response to checkpoint inhibitor therapeutics. Proc Natl Acad Sci USA. 2020;117(24):13428–36.

    CAS  PubMed  Article  Google Scholar 

  199. 199.

    Reichmuth AM, Oberli MA, Jaklenec A, Langer R, Blankschtein D. mRNA vaccine delivery using lipid nanoparticles. Ther Deliv. 2016;7(5):319–34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  200. 200.

    Oberli MA, Reichmuth AM, Dorkin JR, Mitchell MJ, Fenton OS, Jaklenec A, et al. Lipid nanoparticle assisted mRNA delivery for potent cancer immunotherapy. Nano Lett. 2017;17(3):1326–35.

    CAS  PubMed  Article  Google Scholar 

  201. 201.

    Habibi N, Christau S, Ochyl LJ, Fan Z, Hassani Najafabadi A, Kuehnhammer M, et al. Engineered ovalbumin nanoparticles for cancer immunotherapy. Advanced Therapeutics. 2020;3(10):2000100.

    CAS  Article  Google Scholar 

  202. 202.

    Kranz LM, Diken M, Haas H, Kreiter S, Loquai C, Reuter KC, et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature. 2016;534(7607):396–401.

    PubMed  Article  CAS  Google Scholar 

  203. 203.

    Anselmo AC, Mitragotri S. Cell-mediated delivery of nanoparticles: taking advantage of circulatory cells to target nanoparticles. J Control Release. 2014;190:531–41.

    CAS  PubMed  Article  Google Scholar 

  204. 204.

    Agrahari V, Agrahari V, Mitra AK. Next generation drug delivery: circulatory cells-mediated nanotherapeutic approaches. Expert Opin Drug Deliv. 2017;14(3):285–9.

    PubMed  Article  Google Scholar 

  205. 205.

    Zheng Y, Tang L, Mabardi L, Kumari S, Irvine DJ. Enhancing adoptive cell therapy of cancer through targeted delivery of small-molecule immunomodulators to internalizing or noninternalizing receptors. ACS Nano. 2017;11(3):3089–100.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  206. 206.

    Zhao Z, Ukidve A, Gao Y, Kim J, Mitragotri S. Erythrocyte leveraged chemotherapy (ELeCt): Nanoparticle assembly on erythrocyte surface to combat lung metastasis. Sci Adv. 2019;5(11):eaax9250.

  207. 207.

    Ukidve A, Zhao Z, Fehnel A, Krishnan V, Pan DC, Gao Y, et al. Erythrocyte-driven immunization via biomimicry of their natural antigen-presenting function. Proc Natl Acad Sci. 2020;117(30):17727.

    CAS  PubMed  Article  Google Scholar 

  208. 208.

    Huang B, Abraham WD, Zheng Y, Bustamante López SC, Luo SS, Irvine DJ. Active targeting of chemotherapy to disseminated tumors using nanoparticle-carrying T cells. Sci Transl Med. 2015;7(291):291ra94.

  209. 209.

    Stephan MT, Moon JJ, Um SH, Bershteyn A, Irvine DJ. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nat Med. 2010;16(9):1035–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  210. 210.

    Schmid D, Park CG, Hartl CA, Subedi N, Cartwright AN, Puerto RB, et al. T cell-targeting nanoparticles focus delivery of immunotherapy to improve antitumor immunity. Nat Commun. 2017;8(1):1747.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  211. 211.

    Stephan MT, Stephan SB, Bak P, Chen J, Irvine DJ. Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles. Biomaterials. 2012;33(23):5776–87.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  212. 212.

    Tang L, Zheng Y, Melo MB, Mabardi L, Castano AP, Xie YQ, et al. Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery. Nat Biotechnol. 2018;36(8):707–16.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  213. 213.

    Siriwon N, Kim YJ, Siegler E, Chen X, Rohrs JA, Liu Y, et al. CAR-T cells surface-engineered with drug-encapsulated nanoparticles can ameliorate intratumoral T-cell hypofunction. Cancer Immunol Res. 2018;6(7):812.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  214. 214.

    Zhang W, Wang M, Tang W, Wen R, Zhou S, Lee C, et al. Nanoparticle-laden macrophages for tumor-tropic drug delivery. Adv Mater. 2018;30(50):1805557.

    Article  CAS  Google Scholar 

  215. 215.

    Champion JA, Mitragotri S. Role of target geometry in phagocytosis. Proc Natl Acad Sci USA. 2006b;103(13):4930.

    CAS  PubMed  Article  Google Scholar 

  216. 216.

    Shields CW, Evans MA, Wang LLW, Baugh N, Iyer S, Wu D, et al. Cellular backpacks for macrophage immunotherapy. Sci Adv. 2020;6(18):eaaz6579.

  217. 217.

    Brenner JS, Pan DC, Myerson JW, Marcos-Contreras OA, Villa CH, Patel P, et al. Red blood cell-hitchhiking boosts delivery of nanocarriers to chosen organs by orders of magnitude. Nat Commun. 2018;9(1):2684.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  218. 218.

    Zhao Z, Ukidve A, Krishnan V, Fehnel A, Pan DC, Gao Y, et al. Systemic tumour suppression via the preferential accumulation of erythrocyte-anchored chemokine-encapsulating nanoparticles in lung metastases. Nat Biomed Eng. 2020.

  219. 219.

    Layek B, Sehgal D, Argenta PA, Panyam J, Prabha S. Nanoengineering of mesenchymal stem cells via surface modification for efficient cancer therapy. Advanced Therapeutics. 2019;2(9):1900043.

    CAS  Article  Google Scholar 

  220. 220.

    Chu D, Dong X, Shi X, Zhang C, Wang Z. Neutrophil-based drug delivery systems. Adv Mater. 2018;30(22):e1706245.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  221. 221.

    Bisso PW, Gaglione S, Guimarães PPG, Mitchell MJ, Langer R. Nanomaterial interactions with human neutrophils. ACS Biomater Sci Eng. 2018;4(12):4255–65.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  222. 222.

    Xue J, Zhao Z, Zhang L, Xue L, Shen S, Wen Y, et al. Neutrophil-mediated anticancer drug delivery for suppression of postoperative malignant glioma recurrence. Nat Nanotechnol. 2017;12(7):692–700.

    CAS  PubMed  Article  Google Scholar 

  223. 223.

    Wu M, Zhang H, Tie C, Yan C, Deng Z, Wan Q, et al. MR imaging tracking of inflammation-activatable engineered neutrophils for targeted therapy of surgically treated glioma. Nat Commun. 2018;9(1):4777.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  224. 224.

    Mura S, Nicolas J, Couvreur P. Stimuli-responsive nanocarriers for drug delivery. Nat Mater. 2013;12(11):991–1003.

    CAS  PubMed  Article  Google Scholar 

  225. 225.

    Deng Z, Zhen Z, Hu X, Wu S, Xu Z, Chu PK. Hollow chitosan–silica nanospheres as pH-sensitive targeted delivery carriers in breast cancer therapy. Biomaterials. 2011;32(21):4976–86.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  226. 226.

    Liu Y, Qiao L, Zhang S, Wan G, Chen B, Zhou P, et al. Dual pH-responsive multifunctional nanoparticles for targeted treatment of breast cancer by combining immunotherapy and chemotherapy. Acta Biomater. 2018;66:310–24.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  227. 227.

    Li Y, Wu Q, Kang M, Song N, Wang D, Tang BZ. Boosting the photodynamic therapy efficiency by using stimuli-responsive and AIE-featured nanoparticles. Biomaterials. 2020;232:119749.

    CAS  PubMed  Article  Google Scholar 

  228. 228.

    You DG, Deepagan V, Um W, Jeon S, Son S, Chang H, et al. ROS-generating TiO 2 nanoparticles for non-invasive sonodynamic therapy of cancer. Sci Rep. 2016;6(1):1–12.

    Article  CAS  Google Scholar 

  229. 229.

    Wang C, Ye Y, Hu Q, Bellotti A, Gu Z. Tailoring biomaterials for cancer immunotherapy: emerging trends and future outlook. Adv Mater. 2017;29(29):1606036.

    Article  CAS  Google Scholar 

  230. 230.

    Zhang R, Billingsley MM, Mitchell MJ. Biomaterials for vaccine-based cancer immunotherapy. J Control Release. 2018;292:256–76.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  231. 231.

    Liu X, Yan S, Luo Z, Li Z, Wang Y, Tao J, et al. Improving Cancer Immunotherapy Outcomes using Biomaterials. Angew Chem. 2020.

  232. 232.

    Wang H, Mooney DJ. Biomaterial-assisted targeted modulation of immune cells in cancer treatment. Nat Mater. 2018;17(9):761–72.

    CAS  PubMed  Article  Google Scholar 

  233. 233.

    Gammon JM, Dold NM, Jewell CM. Improving the clinical impact of biomaterials in cancer immunotherapy. Oncotarget. 2016;7(13):15421.

    PubMed  PubMed Central  Article  Google Scholar 

  234. 234.

    Cheung AS, Zhang DK, Koshy ST, Mooney DJ. Scaffolds that mimic antigen-presenting cells enable ex vivo expansion of primary T cells. Nat Biotechnol. 2018;36(2):160.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  235. 235.

    Fadel TR, Sharp FA, Vudattu N, Ragheb R, Garyu J, Kim D, et al. A carbon nanotube–polymer composite for T-cell therapy. Nat Nanotechnol. 2014;9(8):639.

    CAS  PubMed  Article  Google Scholar 

  236. 236.

    Li AW, Sobral MC, Badrinath S, Choi Y, Graveline A, Stafford AG, et al. A facile approach to enhance antigen response for personalized cancer vaccination. Nat Mater. 2018;17(6):528–34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  237. 237.

    Wang H, Najibi AJ, Sobral MC, Seo BR, Lee JY, Wu D, et al. Biomaterial-based scaffold for in situ chemo-immunotherapy to treat poorly immunogenic tumors. Nat Commun. 2020;11(1):1–14.

    Article  CAS  Google Scholar 

  238. 238.

    Kearney CJ, Mooney DJ. Macroscale delivery systems for molecular and cellular payloads. Nat Mater. 2013;12(11):1004–17.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  239. 239.

    Chao Y, Chen Q, Liu Z. Smart injectable hydrogels for cancer immunotherapy. Adv Func Mater. 2020;30(2):1902785.

    CAS  Article  Google Scholar 

  240. 240.

    Yang P, Song H, Qin Y, Huang P, Zhang C, Kong D, et al. Engineering dendritic-cell-based vaccines and PD-1 blockade in self-assembled peptide nanofibrous hydrogel to amplify antitumor T-cell immunity. Nano Lett. 2018;18(7):4377–85.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  241. 241.

    Yu S, Wang C, Yu J, Wang J, Lu Y, Zhang Y, et al. Injectable bioresponsive gel depot for enhanced immune checkpoint blockade. Adv Mater. 2018;30(28):1801527.

    Article  CAS  Google Scholar 

  242. 242.

    Panagi M, Voutouri C, Mpekris F, Papageorgis P, Martin MR, Martin JD, et al. TGF-beta inhibition combined with cytotoxic nanomedicine normalizes triple negative breast cancer microenvironment towards anti-tumor immunity. Theranostics. 2020;10(4):1910–22.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  243. 243.

    Parlato S, De Ninno A, Molfetta R, Toschi E, Salerno D, Mencattini A, et al. 3D Microfluidic model for evaluating immunotherapy efficacy by tracking dendritic cell behaviour toward tumor cells. Sci Rep. 2017b;7(1):1093.

    PubMed  PubMed Central  Article  Google Scholar 

  244. 244.

    Xue JW, Zhao ZK, Zhang L, Xue LJ, Shen SY, Wen YJ, et al. Neutrophil-mediated anticancer drug delivery for suppression of postoperative malignant glioma recurrence. Nat Nanotechnol. 2017;12(7):692.

    CAS  PubMed  Article  Google Scholar 

  245. 245.

    You DG, Deepagan VG, Um W, Jeon S, Son S, Chang H, et al. ROS-generating TiO2 nanoparticles for non-invasive sonodynamic therapy of cancer. Sci Rep. 2016b;6:23200.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  246. 246.

    Galsky MD. Bladder cancer in 2017: advancing care through genomics and immune checkpoint blockade. Nat Rev Urol. 2018;15(2):71–2.

    PubMed  Article  PubMed Central  Google Scholar 

  247. 247.

    Arvanitis CD, Ferraro GB, Jain RK. The blood-brain barrier and blood-tumour barrier in brain tumours and metastases. Nat Rev Cancer. 2020;20(1):26–41.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  248. 248.

    Thomas OS, Weber W. Overcoming physiological barriers to nanoparticle delivery-are we there yet? Front Bioeng Biotechnol. 2019;7:415.

    PubMed  PubMed Central  Article  Google Scholar 

  249. 249.

    Morice P, Leary A, Creutzberg C, Abu-Rustum N, Darai E. Endometrial cancer. Lancet. 2016;387(10023):1094–108.

    PubMed  Article  PubMed Central  Google Scholar 

  250. 250.

    Heidegger I, Pircher A, Pichler R. Targeting the tumor microenvironment in renal cell cancer biology and therapy. Front Oncol. 2019;9:490.

    PubMed  PubMed Central  Article  Google Scholar 

  251. 251.

    Wang XW, Thorgeirsson SS. The biological and clinical challenge of liver cancer heterogeneity. Hepat Oncol. 2014;1(4):349–53.

    PubMed  PubMed Central  Article  Google Scholar 

  252. 252.

    Merlino G, Herlyn M, Fisher DE, Bastian BC, Flaherty KT, Davies MA, et al. The state of melanoma: challenges and opportunities. Pigment Cell Melanoma Res. 2016;29(4):404–16.

    PubMed  PubMed Central  Article  Google Scholar 

  253. 253.

    Wang QM, Lian GY, Song Y, Peng ZD, Xu SH, Gong Y. Downregulation of miR-152 contributes to DNMT1-mediated silencing of SOCS3/SHP-1 in non-Hodgkin lymphoma. Cancer Gene Ther. 2019;26(7–8):195–207.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  254. 254.

    Tanaka HY, Kano MR. Stromal barriers to nanomedicine penetration in the pancreatic tumor microenvironment. Cancer Sci. 2018;109(7):2085–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  255. 255.

    Naoum GE, Morkos M, Kim B, Arafat W. Novel targeted therapies and immunotherapy for advanced thyroid cancers. Mol Cancer. 2018;17(1):51.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

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Acknowledgements

Authors acknowledge the use of Biorender.com for making graphical abstract and schematics.

Funding

This work was funded by support from National Institutes of Health (1R01HL143806-01).

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AU, KC, and NK contributed equally. AU, KC, NK, JL, and SM wrote the manuscript.

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Correspondence to Samir Mitragotri.

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SM and AU are inventors on patent applications in the field of tumor immunotherapy (owned and managed by Harvard University).

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Ukidve, A., Cu, K., Kumbhojkar, N. et al. Overcoming biological barriers to improve solid tumor immunotherapy. Drug Deliv. and Transl. Res. (2021). https://doi.org/10.1007/s13346-021-00923-8

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Keywords

  • Solid tumor
  • Immunotherapy
  • Immune modulation
  • Adoptive cell transfer
  • Nanoparticles
  • Biomaterials