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Delivery technologies for cancer immunotherapy

Abstract

Immunotherapy has become a powerful clinical strategy for treating cancer. The number of immunotherapy drug approvals has been increasing, with numerous treatments in clinical and preclinical development. However, a key challenge in the broad implementation of immunotherapies for cancer remains the controlled modulation of the immune system, as these therapeutics have serious adverse effects including autoimmunity and nonspecific inflammation. Understanding how to increase the response rates to various classes of immunotherapy is key to improving efficacy and controlling these adverse effects. Advanced biomaterials and drug delivery systems, such as nanoparticles and the use of T cells to deliver therapies, could effectively harness immunotherapies and improve their potency while reducing toxic side effects. Here, we discuss these research advances, as well as the opportunities and challenges for integrating delivery technologies into cancer immunotherapy, and we critically analyse the outlook for these emerging areas.

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Fig. 1: Paradigms in cancer nanomedicine.
Fig. 2: Barriers to mRNA cancer vaccine delivery to dendritic cells.
Fig. 3: Nanoparticles and nanoscale conjugates and delivery systems for cancer immunotherapy.
Fig. 4: Biomaterials for localized delivery of cancer immunotherapy.
Fig. 5: Delivery approaches for T cell-based immunotherapy.

References

  1. 1.

    Thomas, B., Coates, D., Tzeng, V., Baehner, L. & Boxer, A. Treatment of hairy cell leukemia with recombinant alpha-interferon. Blood 68, 493–497 (1986).

    Google Scholar 

  2. 2.

    Ahmed, S. & Rai, K. Interferon in the treatment of hairy-cell leukemia. Best Pract. Res. Clin. Haematol. 16, 69–81 (2003).

    CAS  PubMed  Google Scholar 

  3. 3.

    Rosenberg, S. A. IL-2: the first effective immunotherapy for human cancer. J. Immunol. 192, 5451–5458 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Lee, S. & Margolin, K. Cytokines in cancer immunotherapy. Cancers (Basel) 3, 3856–3893 (2011).

    Google Scholar 

  5. 5.

    Kirchner, G. I. et al. Pharmacokinetics of recombinant human interleukin-2 in advanced renal cell carcinoma patients following subcutaneous application. Br. J. Clin. Pharmacol. 46, 5–10 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Rosenberg, S. A. et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N. Engl. J. Med. 316, 889–897 (1987).

    CAS  PubMed  Google Scholar 

  7. 7.

    Alwan, L. et al. Comparison of acute toxicity and mortality after two different dosing regimens of high-dose interleukin-2 for patients with metastatic melanoma. Target. Oncol. 9, 63–71 (2014).

    PubMed  Google Scholar 

  8. 8.

    Rosenberg, S. A., Yang, J. C. & Restifo, N. P. Cancer immunotherapy: moving beyond current vaccines. Nat. Med. 10, 909–915 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010).

    CAS  PubMed  Google Scholar 

  10. 10.

    Graff, J. N. & Chamberlain, E. D. Sipuleucel-T in the treatment of prostate cancer: an evidence-based review of its place in therapy. Core Evid. 10, 1–10 (2015).

    CAS  PubMed  Google Scholar 

  11. 11.

    Hodi, F. S. et al. Improved survival with ipilimumab patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).

    CAS  Google Scholar 

  13. 13.

    Fesnak, A. D., June, C. H. & Levine, B. L. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat. Rev. Cancer 16, 566–581 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Porter, D. L. et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci. Transl Med. 7, 1–12 (2015).

    Google Scholar 

  15. 15.

    June, C. H., O’Connor, R. S., Kawalekar, O. U., Ghassemi, S. & Milone, M. C. CAR T cell immunotherapy for human cancer. Science 359, 1361–1365 (2018).

    CAS  PubMed  Google Scholar 

  16. 16.

    Grupp, S. A. et al. Chimeric antigen receptor–modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Couzin-Frankel, J. Cancer immunotherapy. Science 342, 1432–1433 (2013).

    CAS  PubMed  Google Scholar 

  18. 18.

    Maleki Vareki, S., Garrigós, C. & Duran, I. Biomarkers of response to PD-1/PD-L1 inhibition. Crit. Rev. Oncol. Hematol. 116, 116–124 (2017).

    PubMed  Google Scholar 

  19. 19.

    Hay, K. A. et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor–modified T cell therapy. Blood 130, 2295–2306 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Schmidt, C. The benefits of immunotherapy combinations. Nature 552, S67–S69 (2018).

  21. 21.

    Riley, R. S. & Day, E. S. Gold nanoparticle-mediated photothermal therapy: applications and opportunities for multimodal cancer treatment. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 9, e1449 (2017).

    Google Scholar 

  22. 22.

    Menon, S., Shin, S. & Dy, G. Advances in cancer immunotherapy in solid tumors. Cancers (Basel). 8, (1–21 (2016).

    Google Scholar 

  23. 23.

    Williams, A. D. et al. Immunotherapy for breast cancer: current and future strategies. Curr. Surg. Rep. 5, 31 (2017).

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Brown, C. E. et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N. Engl. J. Med. 375, 2561–2569 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Milling, L., Zhang, Y. & Irvine, D. J. Delivering safer immunotherapies for cancer. Adv. Drug Deliv. Rev. 114, 79–101 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    June, C. H., Warshauer, J. T. & Bluestone, J. A. Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat. Med. 23, 540–547 (2017).

    CAS  PubMed  Google Scholar 

  27. 27.

    Wang, C., Ye, Y., Hu, Q., Bellotti, A. & Gu, Z. Tailoring biomaterials for cancer immunotherapy: emerging trends and future outlook. Adv. Mater. 29, 1–24 (2017).

    Google Scholar 

  28. 28.

    Miller, A. D. Lipid-based nanoparticles in cancer diagnosis and therapy. J. Drug. Deliv. 2013, 1–9 (2013).

    Google Scholar 

  29. 29.

    Liechty, W. B., Kryscio, D. R., Slaughter, B. V. & Peppas, N. A. Polymers for drug delivery systems. Annu. Rev. Chem. Biomol. Eng. 1, 149–173 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Moon, J. J., Huang, B. & Irvine, D. J. Engineering nano- and microparticles to tune immunity. Adv. Mater. 24, 3724–3746 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Toy, R. & Roy, K. Engineering nanoparticles to overcome barriers to immunotherapy. Bioeng. Transl Med. 1, 47–62 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Shao, K. et al. Nanoparticle-based immunotherapy for cancer. ACS Nano 9, 16–30 (2015).

    CAS  PubMed  Google Scholar 

  33. 33.

    Wilson, J. T. et al. pH-responsive nanoparticle vaccines for dual-delivery of antigens and immunostimulatory oligonucleotides. ACS Nano 7, 3912–3925 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Zhang, C. et al. A light responsive nanoparticle-based delivery system using pheophorbide a graft polyethylenimine for dendritic cell-based cancer immunotherapy. Mol. Pharm. 14, 1760–1770 (2017).

    CAS  PubMed  Google Scholar 

  35. 35.

    Pan, Y. et al. Mechanogenetics for the remote and noninvasive control of cancer immunotherapy. Proc. Natl Acad. Sci. USA 115, 992–997 (2018).

    CAS  PubMed  Google Scholar 

  36. 36.

    Ali, O. A., Huebsch, N., Cao, L., Dranoff, G. & Mooney, D. J. Infection-mimicking materials to program dendritic cells in situ. Nat. Mater. 8, 151–158 (2009). In this paper, implantable polymeric scaffolds were designed to release cytokines to recruit host dendritic cells — as well as present cancer antigens and danger signals to activate those cells — as a means to generate specific and protective antitumour immunity.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Stephan, S. B. et al. Biopolymer implants enhance the efficacy of adoptive T cell therapy. Nat. Biotechnol. 33, 97–101 (2015). In this paper, polymeric scaffolds coated with collagen-mimetic peptides were used to bind and deliver antigen-specific T cells locally within the tumour microenvironment, demonstrating that these biomaterials have the potential to maximize the potency of immunotherapy for solid tumour applications.

    CAS  PubMed  Google Scholar 

  38. 38.

    Ye, Y. et al. Synergistic transcutaneous immunotherapy enhances antitumor immune responses through delivery of checkpoint inhibitors. ACS Nano 10, 8956–8963 (2016).

    CAS  PubMed  Google Scholar 

  39. 39.

    Krishnamurthy, A. & Jimeno, A. Bispecific antibodies for cancer therapy: a review. Pharmacol. Ther. 185, 122–134 (2018).

    CAS  PubMed  Google Scholar 

  40. 40.

    Lawler, S., Speranza, M., Cho, C. & Chiocca, A. Oncolytic viruses in cancer treatment. JAMA Oncol. 3, 841–849 (2017).

    PubMed  Google Scholar 

  41. 41.

    Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Webb, E. S. et al. Immune checkpoint inhibitors in cancer therapy. J. Biomed. Res. 32, 317–326 (2017).

    Google Scholar 

  43. 43.

    Granier, C. et al. Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer. ESMO Open 2, e000213 (2017).

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    Alsaab, H. O. et al. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front. Pharmacol. 8, 1–15 (2017).

    Google Scholar 

  45. 45.

    Munn, D. H. & Bronte, V. Immune suppressive mechanisms in the tumor microenvironment. Curr. Opin. Immunol. 39, 1–6 (2016).

    CAS  PubMed  Google Scholar 

  46. 46.

    Blank, C. et al. Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell responses in vitro. Int. J. Cancer 119, 317–327 (2006).

    CAS  PubMed  Google Scholar 

  47. 47.

    Arce Vargas, F. et al. Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell 33, 649–663 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Du, X. et al. A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy. Cell Res. 28, 416–432 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Simpson, T. R. et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti–CTLA-4 therapy against melanoma. J. Exp. Med. 210, 1695–1710 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Ellis, P., Vella, E. & Ung, Y. Immune checkpoint inhibitors for patients with advanced non–small-cell lung cancer: a systematic review. Clin. Lung Cancer 18, 444–459 (2017).

    CAS  PubMed  Google Scholar 

  51. 51.

    Friedman, C., Proverbs-Singh, T. & Powtow, M. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. JAMA Oncol. 2, 1346–1353 (2016).

    PubMed  Google Scholar 

  52. 52.

    Naidoo, J. et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J. Clin. Oncol. 35, 709–717 (2017).

    CAS  PubMed  Google Scholar 

  53. 53.

    Byun, D. J., Wolchok, J. D., Rosenberg, L. M. & Girotra, M. Cancer immunotherapy-immune checkpoint blockade and associated endocrinopathies. Nat. Rev. Endocrinol. 13, 195–207 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Restifo, N. P., Smyth, M. J. & Snyder, A. Acquired resistance to immunotherapy and future challenges. Nat. Rev. Cancer 16, 121–126 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Garg, A. D., Coulie, P. G., Van den Eynde, B. J. & Agostinis, P. Integrating next-generation dendritic cell vaccines into the current cancer immunotherapy landscape. Trends Immunol. 38, 577–593 (2017).

    CAS  PubMed  Google Scholar 

  56. 56.

    Dillman, R. O. Is there a role for therapeutic cancer vaccines in the age of checkpoint inhibitors? Hum. Vaccin. Immunother. 13, 528–532 (2017).

    PubMed  Google Scholar 

  57. 57.

    Joyce, J. & Fearon, D. T cell exclusion, immune privilege, and the tumor microenvironment. Science 348, 74–80 (2015).

    CAS  PubMed  Google Scholar 

  58. 58.

    Katze, M. G., He, Y. & Gale, M. Viruses and interferon: a fight for supremacy. Nat. Rev. Immunol. 2, 675–687 (2002).

    CAS  PubMed  Google Scholar 

  59. 59.

    Sun, T. et al. Inhibition of tumor angiogenesis by interferon-γ by suppression of tumor-associated macrophage differentiation. Oncol. Res. 21, 227–235 (2014).

    CAS  PubMed  Google Scholar 

  60. 60.

    He, T., Tang, C., Xu, S., Moyana, T. & Xiang, J. Interferon gamma stimulates cellular maturation of dendritic cell line DC2.4 leading to induction of efficient cytotoxic T cell responses and antitumor immunity. Cell. Mol. Immunol. 4, 105–111 (2007).

    CAS  PubMed  Google Scholar 

  61. 61.

    Müller, L., Aigner, P. & Stoiber, D. Type I interferons and natural killer cell regulation in cancer. Front. Immunol. 8, 1–11 (2017).

    Google Scholar 

  62. 62.

    Enomoto, H. et al. The in vivo antitumor effects of type I-interferon against hepatocellular carcinoma: the suppression of tumor cell growth and angiogenesis. Sci. Rep 7, 12189 (2017).

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Cox, M. A., Harrington, L. E. & Zajac, A. J. Cytokines and the inception of CD8 T cell responses. Trends Immunol. 32, 180–186 (2012).

    Google Scholar 

  64. 64.

    Ben-Sasson, S. Z. et al. IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation. Proc. Natl Acad. Sci. USA 106, 7119–7124 (2009).

    CAS  PubMed  Google Scholar 

  65. 65.

    Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol. 3, 133–146 (2003).

    CAS  PubMed  Google Scholar 

  66. 66.

    Itoh, K. & Hirohata, S. The role of IL-10 in human B cell activation, proliferation, and differentiation. J. Immunol. 154, 4341–4350 (1995).

    CAS  PubMed  Google Scholar 

  67. 67.

    Yan, W.-L., Shen, K.-Y., Tien, C.-Y., Chen, Y.-A. & Liu, S.-J. Recent progress in GM-CSF-based cancer immunotherapy. Immunotherapy 9, 347–360 (2017).

    CAS  PubMed  Google Scholar 

  68. 68.

    Tanaka, J., Mielcarek, M. & Torok-Storb, B. Impaired induction of the CD28-responsive complex in granulocyte colony-stimulating factor mobilized CD4 T cells. Blood 91, 347–352 (1998).

    CAS  PubMed  Google Scholar 

  69. 69.

    Mehta, H. M., Malandra, M. & Corey, S. J. G-CSF and GM-CSF in neutropenia. J. Immunol. 195, 1341–1349 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Uhl, M. et al. SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Res. 64, 7954–7961 (2004).

    CAS  PubMed  Google Scholar 

  71. 71.

    Fu, J. et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci. Transl Med. 7, 283ra52 (2015).

    PubMed  PubMed Central  Google Scholar 

  72. 72.

    Chi, H. et al. Anti-tumor activity of toll-like receptor 7 agonists. Front. Pharmacol. 8, 1–10 (2017).

    Google Scholar 

  73. 73.

    Perna, S. K. et al. Interleukin-7 mediates selective expansion of tumor-redirected cytotoxic T lymphocytes (CTLs) without enhancement of regulatory T cell inhibition. Clin. Cancer Res. 20, 131–139 (2014).

    CAS  PubMed  Google Scholar 

  74. 74.

    Berger, S. C. et al. Safety and immunologic effects of IL-15 administration in nonhuman primates. Blood 114, 2417–2426 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Hasan, A. N. et al. Soluble and membrane-bound interleukin (IL)-15 Rα/IL-15 complexes mediate proliferation of high-avidity central memory CD8+T cells for adoptive immunotherapy of cancer and infections. Clin. Exp. Immunol. 186, 249–265 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Chapuis, A. G. et al. Combined IL-21–primed polyclonal CTL plus CTLA4 blockade controls refractory metastatic melanoma in a patient. J. Exp. Med. 213, 1133–1139 (2016).

    PubMed  PubMed Central  Google Scholar 

  77. 77.

    Lim, W. A. & June, C. H. The principles of engineering immune cells to treat cancer. Cell 168, 724–740 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Scholler, J. et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci. Transl Med. 4, 132ra53 (2012).

    PubMed  PubMed Central  Google Scholar 

  79. 79.

    Schuster, S. J. et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N. Engl. J. Med. 377, 2545–2554 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Levine, B. L., Miskin, J., Wonnacott, K. & Keir, C. Global manufacturing of CAR T cell therapy. Mol. Ther. Methods Clin. Dev. 4, 92–101 (2017).

    CAS  PubMed  Google Scholar 

  81. 81.

    Davila, M. L. & Brentjens, R. J. CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B cell acute lymphoblastic leukemia. Clin. Adv. Hematol. Oncol. 14, 802–808 (2016).

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531–2544 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Frigault, M. J. et al. Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells. Cancer Immunol. Res. 3, 356–367 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    O’Rourke, D. M. et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci. Transl Med. 9, 1–35 (2017).

    Google Scholar 

  86. 86.

    Posey, A. D. et al. Engineered CAR T cells targeting the cancer-associated Tn-glycoform of the membrane mucin MUC1 control adenocarcinoma. Immunity 44, 1444–1454 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Bailey, S. R. et al. Human CD26high T cells elicit tumor immunity against multiple malignancies via enhanced migration and persistence. Nat. Commun. 8, 1961 (2017).

    PubMed  PubMed Central  Google Scholar 

  88. 88.

    Ruella, M. et al. Overcoming the immunosuppressive tumor microenvironment of Hodgkin lymphoma using chimeric antigen receptor T cells. Cancer Discov. 7, 1154–1167 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Fitzgerald, J. C. et al. Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Crit. Care. Med. 45, e124–e131 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Van Den Berg, J. H. et al. Case report of a fatal serious adverse event upon administration of T cells transduced with a MART-1-specific T cell receptor. Mol. Ther. 23, 1541–1550 (2015).

    PubMed  PubMed Central  Google Scholar 

  91. 91.

    Migliorini, D. et al. CAR T cell therapies in glioblastoma: a first look. Clin. Cancer Res. 24, 535–540 (2018).

    CAS  PubMed  Google Scholar 

  92. 92.

    Hege, K. M. et al. Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer. J. Immunother. Cancer 5, 1–14 (2017).

    Google Scholar 

  93. 93.

    Cohen, M. & Reiter, Y. T-cell receptor-like antibodies: targeting the intracellular proteome therapeutic potential and clinical applications. Antibodies 2, 517–534 (2013).

    Google Scholar 

  94. 94.

    Linnemann, C. et al. High-throughput identification of antigen-specific TCRs by TCR gene capture. Nat. Med. 19, 1534–1541 (2013).

    CAS  PubMed  Google Scholar 

  95. 95.

    Cameron, B. J. et al. Identification of a Titin-derived HLA-A1 – presented peptide as a cross-reactive target for engineered MAGE A3 – directed T cells. Sci. Transl Med. 5, 197ra103 (2013).

    PubMed  PubMed Central  Google Scholar 

  96. 96.

    Linette, G. P. et al. Cardiovascular toxicity and titin cross-reactivity of af fi nity-enhanced T cells in myeloma and melanoma. Blood 122, 863–872 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Peggs, K. S., Quezada, S. A. & Allison, J. P. Cancer immunotherapy: co-stimulatory agonists and co-inhibitory antagonists. Clin. Exp. Immunol. 157, 9–19 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Croft, M. Co-stimulatory members of the TNFR family: keys to effective T cell immunity? Nat. Rev. Immunol. 3, 609–620 (2003).

    CAS  PubMed  Google Scholar 

  99. 99.

    Chester, C., Sanmamed, M. F., Wang, J. & Melero, I. Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. Blood 131, 49–57 (2018).

    CAS  PubMed  Google Scholar 

  100. 100.

    Tolcher, A. W. et al. Phase Ib study of utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in combination with pembrolizumab (MK-3475) in patients with advanced solid tumors. Clin. Cancer Res. 23, 5349–5357 (2017).

    CAS  PubMed  Google Scholar 

  101. 101.

    Segal, N. H. et al. Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin. Cancer Res. 23, 1929–1936 (2017).

    CAS  PubMed  Google Scholar 

  102. 102.

    Buchan, S. L., Rogel, A. & Al-Shamkhani, A. The immunobiology of CD27 and OX40 and their potential as targets for cancer immunotherapy. Blood 131, 39–48 (2018).

    CAS  PubMed  Google Scholar 

  103. 103.

    Zhang, P. et al. Agonistic anti-4-1BB antibody promotes the expansion of natural regulatory T cells while maintaining Foxp3 expression. Scand. J. Immunol. 66, 435–440 (2007).

    CAS  PubMed  Google Scholar 

  104. 104.

    Zhang, Y., Li, N., Suh, H. & Irvine, D. J. Nanoparticle anchoring targets immune agonists to tumors enabling anti-cancer immunity without systemic toxicity. Nat. Commun. 9, 6 (2018).

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    Guo, C. et al. Therapeutic cancer vaccines; past, present and future. Adv. Cancer Res. 119, 421–475 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Chiang, C., Coukos, G. & Kandalaft, L. Whole tumor antigen vaccines: where are we? Vaccines 3, 344–372 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Srivatsan, S. et al. Allogeneic tumor cell vaccines: the promise and limitations in clinical trials. Hum. Vaccin. Immunother. 10, 52–63 (2014).

    CAS  PubMed  Google Scholar 

  108. 108.

    Mullard, A. The cancer vaccine resurgence. Nat. Rev. Drug Discov. 15, 663–665 (2016).

    CAS  PubMed  Google Scholar 

  109. 109.

    Butterfield, L. H. Dendritic cells in cancer immunotherapy clinical trials: are we making progress? Front. Immunol. 4, 1–7 (2013).

    CAS  Google Scholar 

  110. 110.

    Schreibelt, G. et al. Effective clinical responses in metastatic melanoma patients after vaccination with primary myeloid dendritic cells. Clin. Cancer Res. 22, 2155–2166 (2016).

    CAS  PubMed  Google Scholar 

  111. 111.

    Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Yang, B., Jeang, J., Yang, A., Wu, T. C. & Hung, C.-F. DNA vaccine for cancer immunotherapy. Hum. Vaccin. Immunother. 10, 3153–3164 (2015).

    PubMed Central  Google Scholar 

  113. 113.

    McNamara, M. A., Nair, S. K. & Holl, E. K. RNA-based vaccines in cancer immunotherapy. J. Immunol. Res. 2015, 794528 (2015).

    PubMed  PubMed Central  Google Scholar 

  114. 114.

    Liu, M. A. DNA vaccines: an historical perspective and view to the future. Immunol. Rev. 239, 62–84 (2011).

    CAS  PubMed  Google Scholar 

  115. 115.

    Schlake, T., Thess, A., Fotin-Mleczek, M. & Kallen, K. J. Developing mRNA-vaccine technologies. RNA Biol. 9, 1319–1330 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Kauffman, K. J., Webber, M. J. & Anderson, D. G. Materials for non-viral intracellular delivery of messenger RNA therapeutics. J. Control. Release 240, 227–234 (2016).

    CAS  PubMed  Google Scholar 

  117. 117.

    Li, L., Goedegebuure, S. P. & Gillanders, W. E. Preclinical and clinical development of neoantigen vaccines. Ann. Oncol. 28, xii11–xii17 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Lauss, M. et al. Mutational and putative neoantigen load predict clinical benefit of adoptive T cell therapy in melanoma. Nat. Commun. 8, 1738 (2017).

    PubMed  PubMed Central  Google Scholar 

  119. 119.

    Phua, K., Nair, S. & Leong, K. Messenger RNA (mRNA) nanoparticle tumour vaccination. Nanoscale 6, 7715–7729 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Zhu, G., Zhang, F., Ni, Q., Niu, G. & Chen, X. Efficient nanovaccine delivery in cancer immunotherapy. ACS Nano 11, 2387–2392 (2017).

    CAS  PubMed  Google Scholar 

  121. 121.

    Binnewies, M. et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 24, 541–550 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Song, W. et al. Synergistic and low adverse effect cancer immunotherapy by immunogenic chemotherapy and locally expressed PD-L1 trap. Nat. Commun. 9, 2237 (2018).

    PubMed  PubMed Central  Google Scholar 

  123. 123.

    Wong, C. et al. Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc. Natl Acad. Sci. USA 108, 2426–2431 (2010).

    Google Scholar 

  124. 124.

    Sahay, G. et al. Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling. Nat. Biotechnol. 31, 653–658 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Lopez-bertoni, H. et al. Bioreducible polymeric nanoparticles containing multiplexed cancer stem cell-regulating miRNAs inhibit glioblastoma growth and prolong survival. Nano Lett. 18, 4086–4094 (2018).

    CAS  PubMed  Google Scholar 

  126. 126.

    Engel, A. L., Holt, G. E. & Lu, H. The pharmacokinectics of toll-like receptor agonists and the impact on the immune system. Expert Rev. Clin. Pharmacol. 4, 275–289 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Whiteside, T. L., Demaria, S., Rodriguez-Ruiz, M. E., Zarour, H. M. & Melero, I. Emerging opportunities and challenges in cancer immunotherapy. Clin. Cancer Res. 22, 1845–1855 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Lyon, J. G., Mokarram, N., Saxena, T., Carroll, S. L. & Bellamkonda, R. V. Engineering challenges for brain tumor immunotherapy. Adv. Drug Deliv. Rev. 114, 19–32 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Sagiv-Barfi, I. et al. Eradication of spontaneous malignancy by local immunotherapy. Sci. Transl Med. 10, eaan4488 (2018).

    PubMed  PubMed Central  Google Scholar 

  130. 130.

    Hu, B. et al. Augmentation of antitumor immunity by human and mouse CAR T cells secreting IL-18. Cell Rep. 20, 3025–3033 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Matsumura, Y. & Maeda, H. A. New concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 46, 6387–6392 (1986).

    CAS  PubMed  Google Scholar 

  132. 132.

    Gerlowski, L. E. & Jain, R. K. Microvascular permeability of normal and neoplastic tissues. Microvasc. Res. 31, 288–305 (1986).

    CAS  PubMed  Google Scholar 

  133. 133.

    Xu, X., Ho, W., Zhang, X., Bertrand, N. & Farokhzad, O. Cancer nanomedicine: from targeted delivery to combination therapy. Trends Mol. Med. 21, 223–232 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Bertrand, N., Wu, J., Xu, X., Kamaly, N. & Farokhzad, O. C. Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv. Drug Deliv. Rev. 66, 2–25 (2014).

    CAS  PubMed  Google Scholar 

  135. 135.

    Mitchell, M. J., Jain, R. K. & Langer, R. Engineering and physical sciences in oncology: challenges and opportunities. Nat. Rev. Cancer 17, 659–675 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Wilhelm, S. et al. Analysis of nanoparticle delivery to tumors. Nat. Rev. Mater. 1, 160104 (2016).

    Google Scholar 

  137. 137.

    Ramanathan, R. K. et al. Correlation between ferumoxytol uptake in tumor lesions by MRI and response to nanoliposomal irinotecan in patients with advanced solid tumors: a pilot study. Clin. Cancer Res. 23, 3638–3648 (2017).

    CAS  PubMed  Google Scholar 

  138. 138.

    Lee, H. et al. 64Cu-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. 23, 4190–4202 (2017).

    CAS  PubMed  Google Scholar 

  139. 139.

    Mishra, P., Nayak, B. & Dey, R. K. PEGylation in anti-cancer therapy: an overview. Asian J. Pharm. Sci. 11, 337–348 (2016).

    Google Scholar 

  140. 140.

    Valcourt, D. M. et al. Advances in targeted nanotherapeutics: from bioconjugation to biomimicry. Nano Res. 11, 4999–5016 (2018).

    CAS  Google Scholar 

  141. 141.

    Riley, R. S. & Day, E. S. Frizzled7 antibody-functionalized nanoshells enable multivalent binding for Wnt signaling inhibition in triple negative breast cancer cells. Small 13, 1–10 (2017).

    Google Scholar 

  142. 142.

    Bartlett, D. W., Su, H., Hildebrandt, I. J., Weber, W. A. & Davis, M. E. Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proc. Natl Acad. Sci. USA 104, 15549–15554 (2007).

    CAS  PubMed  Google Scholar 

  143. 143.

    Wang, C., Ye, Y., Hochu, G. M., Sadeghifar, H. & Gu, Z. Enhanced cancer immunotherapy by microneedle patch-assisted delivery of anti-PD1 antibody. Nano Lett. 16, 2334–2340 (2016). In this paper, microneedle patches were designed to degrade and locally deliver anti-PD-1 antibodies in response to the acidic tumour microenvironment, demonstrating that pH-responsive materials can enable precise control over the local delivery of immunotherapeutics to melanoma.

    CAS  PubMed  Google Scholar 

  144. 144.

    Liu, Y. et al. In situ modulation of dendritic cells by injectable thermosensitive hydrogels for cancer vaccines in mice. Biomacromolecules 15, 3836–3845 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Schmid, D. et al. T cell-targeting nanoparticles focus delivery of immunotherapy to improve antitumor immunity. Nat. Commun. 8, 1747 (2017). In this paper, polymeric nanoparticles were loaded with immunotherapeutics and coated with antibody fragments to target specific T cells in circulation, showing that delivery via particle binding to endogenous immune cells induces stronger antitumour effects than free drug.

    PubMed  PubMed Central  Google Scholar 

  146. 146.

    Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008).

    CAS  PubMed  Google Scholar 

  147. 147.

    Mitchell, M. J., Wayne, E. C., Rana, K., Schaffer, C. B. & King, M. R. TRAIL-coated leukocytes that kill cancer cells in the circulation. Proc. Natl. Acad. Sci. USA 111, 930–935 (2014).

    CAS  PubMed  Google Scholar 

  148. 148.

    Wayne, E. C. et al. TRAIL-coated leukocytes that prevent the bloodborne metastasis of prostate cancer. J. Control. Release 223, 215–223 (2016).

    CAS  PubMed  Google Scholar 

  149. 149.

    Mitchell, M. J., Chen, C. S., Ponmudi, V., Hughes, A. D. & King, M. R. E-Selectin liposomal and nanotube-targeted delivery of doxorubicin to circulating tumor cells. J. Control. Release 160, 609–617 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Hajj, K. A. & Whitehead, K. A. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat. Rev. Mater. 2, 1–17 (2017).

    Google Scholar 

  151. 151.

    Zámec˘ník, J., Vargová, L., Homola, A., Kodet, R. & Syková, E. Extracellular matrix glycoproteins and diffusion barriers in human astrocytic tumours. Neuropathol. Appl. Neurobiol. 30, 338–350 (2004).

    Google Scholar 

  152. 152.

    Lorenz, C. et al. Protein expression from exogenous mRNA: uptake by receptor-mediated endocytosis and trafficking via the lysosomal pathway. RNA Biol. 8, 627–636 (2011).

    CAS  PubMed  Google Scholar 

  153. 153.

    Yin, H. et al. Non-viral vectors for gene-based therapy. Nat. Rev. Genet. 15, 541–555 (2014).

    CAS  PubMed  Google Scholar 

  154. 154.

    Whitehead, K. A., Langer, R. & Anderson, D. G. Knocking down barriers: advances in siRNA delivery. Nat. Rev. Drug Discov. 8, 129–138 (2009).

    CAS  PubMed  Google Scholar 

  155. 155.

    Oberli, M. A. et al. Lipid nanoparticle assisted mRNA delivery for potent cancer immunotherapy. Nano Lett. 17, 1326–1335 (2017). In this paper, a library of ionizable lipid nanoparticles was developed to deliver mRNA vaccines to immune cells and induce strong cytotoxic T cell responses. This article shows that nanoparticle design parameters, such as ionizable lipid structure and formulation parameters, modulate the ability of nanoparticles to successfully deliver mRNA vaccines.

    CAS  PubMed  Google Scholar 

  156. 156.

    Kranz, L. M. et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534, 396–401 (2016). This paper details the development of a nanoparticle-based RNA cancer vaccine that — through adjusting the negative net charge of nanoparticles rather than incorporating targeting ligands — preferentially targets dendritic cells in vivo upon systemic administration. The nanoparticle delivery system induced durable type I interferon-dependent antigen-specific immunity in mouse tumour models and induced strong antigen-specific T cell responses in patients with melanoma in a phase I dose-escalation clinical trial.

    PubMed  Google Scholar 

  157. 157.

    Giacca, M. & Zacchigna, S. VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond. Gene Ther. 19, 622–629 (2012).

    CAS  PubMed  Google Scholar 

  158. 158.

    Ramani, K., Hassan, Q., Venkiah, B., Hasnain, S. & Sarkar, D. P. Site-specific gene delivery in vivo through engineered Sendai. Proc. Natl Acad. Sci. USA 95, 11886–11890 (1998).

    CAS  PubMed  Google Scholar 

  159. 159.

    Nayak, S. & Herzog, R. W. Progress and prospects: immune responses to viral vectors. Gene Ther. 17, 295–304 (2010).

    CAS  PubMed  Google Scholar 

  160. 160.

    Ziller, A. et al. Incorporation of mRNA in lamellar lipid matrices for parenteral administration. Mol. Pharm. 15, 642–651 (2018).

    CAS  PubMed  Google Scholar 

  161. 161.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02410733?term=NCT02410733&rank=1 (2018).

  162. 162.

    Landesman-Milo, D. & Peer, D. Toxicity profiling of several common RNAi-based nanomedicines: a comparative study. Drug Deliv. Transl Res. 4, 96–103 (2014).

    CAS  Google Scholar 

  163. 163.

    Lv, H., Zhang, S., Wang, B., Cui, S. & Yan, J. Toxicity of cationic lipids and cationic polymers in gene delivery. J. Control. Release 114, 100–109 (2006).

    CAS  PubMed  Google Scholar 

  164. 164.

    Ma, Z. et al. Cationic lipids enhance siRNA-mediated interferon response in mice. Biochem. Biophys. Res. Commun. 330, 755–759 (2005).

    CAS  PubMed  Google Scholar 

  165. 165.

    Kauffman, K. J. et al. Optimization of lipid nanoparticle formulations for mRNA delivery in vivo with fractional factorial and definitive screening designs. Nano Lett. 15, 7300–7306 (2015).

    CAS  PubMed  Google Scholar 

  166. 166.

    Huotari, J. & Helenius, A. Endosome maturation. EMBO J. 30, 3481–3500 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Zelphati, O. & Szoka, F. C. Mechanism of oligonucleotide release from cationic liposomes. Proc. Natl Acad. Sci. USA 93, 11493–11498 (1996).

    CAS  PubMed  Google Scholar 

  168. 168.

    Hafez, I. M., Maurer, N. & Cullis, P. R. On the mechanism whereby cationic lipids promote intracellular delivery of polynucleic acids. Gene Ther. 8, 1188–1196 (2001).

    CAS  PubMed  Google Scholar 

  169. 169.

    Walsh, C., Nguyen, J., Tiffany, M. & Szoka, F. Synthesis, characterization and evaluation of ionizable lysine-based lipids for siRNA delivery. Bioconjug. Chem. 24, 36–43 (2013).

    CAS  PubMed  Google Scholar 

  170. 170.

    Chahal, J. S. et al. An RNA nanoparticle vaccine against Zika virus elicits antibody and CD8+ T cell responses in a mouse model. Sci. Rep. 7, 252 (2017).

    PubMed  PubMed Central  Google Scholar 

  171. 171.

    Chahal, J. S. et al. Dendrimer-RNA nanoparticles generate protective immunity against lethal Ebola, H1N1 influenza, and Toxoplasma gondii challenges with a single dose. Proc. Natl Acad. Sci. USA 113, E4133–E4142 (2016).

    CAS  PubMed  Google Scholar 

  172. 172.

    Johansen, P., Mohanan, D., Martínez-Gómez, J. M., Kündig, T. M. & Gander, B. Lympho-geographical concepts in vaccine delivery. J. Control. Release 148, 56–62 (2010).

    CAS  PubMed  Google Scholar 

  173. 173.

    Vartak, A. & Sucheck, S. Recent advances in subunit vaccine carriers. Vaccines 4, 12 (2016).

    PubMed Central  Google Scholar 

  174. 174.

    Keler, T., He, L., Ramakrishna, V. & Champion, B. Antibody-targeted vaccines. Oncogene 26, 3758–3767 (2007).

    CAS  PubMed  Google Scholar 

  175. 175.

    Liu, H. et al. Structure-based programming of lymph-node targeting in molecular vaccines. Nature 507, 519–522 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Moynihan, K. D. et al. Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses. Nat. Med. 22, 1402–1410 (2016). This paper presents a powerful combination of immunotherapeutics, including a tumour antigen-targeting antibody, recombinant IL-2, an anti-PD-1 antibody and a T cell vaccine, that is used to recruit several types of immune cell to elicit diverse immune responses and eradicate established tumours in vivo with substantial improvements over treatment with the individual agents.

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Ishihara, J. et al. Matrix-binding checkpoint immunotherapies enhance antitumor efficacy and reduce adverse events. Sci. Transl Med. 9, eaan0401 (2017). In this paper, matrix-binding molecular conjugates were used to locally deliver checkpoint blockade antibodies to tumours and to induce systemic antitumour immunity, providing a way to reduce the systemic side effects typically associated with these immunotherapeutics.

    PubMed  Google Scholar 

  178. 178.

    Vonderheide, R. H. et al. Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J. Clin. Oncol. 25, 876–883 (2007).

    CAS  PubMed  Google Scholar 

  179. 179.

    Sanderson, K. et al. Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and montanide ISA 51 for patients with resected stages III and IV melanoma. J. Clin. Oncol. 23, 741–750 (2005).

    CAS  PubMed  Google Scholar 

  180. 180.

    Fransen, M. F., Van Der Sluis, T. C., Ossendorp, F., Arens, R. & Melief, C. J. M. Controlled local delivery of CTLA-4 blocking antibody induces CD8+T cell-dependent tumor eradication and decreases risk of toxic side effects. Clin. Cancer Res. 19, 5381–5389 (2013).

    CAS  PubMed  Google Scholar 

  181. 181.

    Fransen, M. F., Sluijter, M., Morreau, H., Arens, R. & Melief, C. J. M. Local activation of CD8 T cells and systemic tumor eradication without toxicity via slow release and local delivery of agonistic CD40 antibody. Clin. Cancer Res. 17, 2270–2280 (2011).

    CAS  PubMed  Google Scholar 

  182. 182.

    Rahimian, S. et al. Polymeric microparticles for sustained and local delivery of antiCD40 and antiCTLA-4 in immunotherapy of cancer. Biomaterials 61, 33–40 (2015).

    CAS  PubMed  Google Scholar 

  183. 183.

    Graham, B. S. et al. Immunization with cocktail of HIV-derived peptides in montanide ISA-51 is immunogenic, but causes sterile abscesses and unacceptable reactogenicity. PLOS ONE 5, e11995 (2010).

    PubMed  PubMed Central  Google Scholar 

  184. 184.

    Kleindienst, P. & Brocker, T. Endogenous dendritic cells are required for amplification of T cell responses induced by dendritic cell vaccines in vivo. J. Immunol. 170, 2817–2823 (2003).

    CAS  PubMed  Google Scholar 

  185. 185.

    Kim, J. et al. Injectable, spontaneously assembling, inorganic scaffolds modulate immune cells in vivo and increase vaccine efficacy. Nat. Biotechnol. 33, 64–72 (2015). In this paper, injectable, spontaneously assembling silica rod-based scaffolds were engineered to release inflammatory signals and adjuvants as a means to recruit dendritic cells and increase vaccine efficacy compared with bolus controls, providing a minimally invasive approach that does not require the surgical implantation needed for other scaffold-based approaches.

    CAS  PubMed  Google Scholar 

  186. 186.

    Ali, O. A., Emerich, D., Dranoff, G. & Mooney, D. J. In situ regulation of DC subsets and T cells mediates tumor regression in mice. Sci. Transl Med. 1, 8ra19 (2010).

    Google Scholar 

  187. 187.

    Gu, L. & Mooney, D. J. Biomaterials and emerging anticancer therapeutics: engineering the microenvironment. Nat. Rev. Cancer 16, 56–66 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 188.

    Ali, O. A., Tayalia, P., Shvartsman, D., Lewen, S. & Mooney, D. Inflammatory cytokines presented from polymer matrices differentially generate and activate DCs in situ. Adv. Funct. Mater. 23, 4621–4628 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189.

    Ali, O. A. et al. Identification of immune factors regulating antitumor immunity using polymeric vaccines with multiple adjuvants. Cancer Res. 74, 1670–1681 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. 190.

    Ali, O. A. et al. The efficacy of intracranial PLG-based vaccines is dependent on direct implantation into brain tissue. J. Control. Release 154, 249–257 (2011).

    CAS  PubMed  Google Scholar 

  191. 191.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01753089?term=NCT01753089&rank=1 (2018).

  192. 192.

    Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).

    CAS  PubMed  Google Scholar 

  193. 193.

    Hori, Y., Winans, A. M., Huang, C. C., Horrigan, E. M. & Irvine, D. J. Injectable dendritic cell-carrying alginate gels for immunization and immunotherapy. Biomaterials 29, 3671–3682 (2008).

    CAS  PubMed  Google Scholar 

  194. 194.

    Koshy, S. T., Ferrante, T. C., Lewin, S. A. & Mooney, D. J. Injectable, porous, and cell-responsive gelatin cryogels. Biomaterials 35, 2477–2487 (2014).

    CAS  PubMed  Google Scholar 

  195. 195.

    Bencherif, S. A. et al. Injectable cryogel-based whole-cell cancer vaccines. Nat. Commun. 6, 1–13 (2015).

    Google Scholar 

  196. 196.

    Li, A. W. et al. A facile approach to enhance antigen response for personalized cancer vaccination. Nat. Mater. 17, 1–7 (2018).

    CAS  Google Scholar 

  197. 197.

    Xia, T. et al. Polyethyleneimine coating enhances the cellular uptake of mesoporous silica nanoparticles and allows safe delivery of siRNA and DNA constructs. ACS Nano 3, 3273–3286 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. 198.

    Garcia-Bennett, A. E. et al. Synthesis toxicology and potential of ordered mesoporous materials in nanomedicine. Nanomedicine 6, 867–877 (2011).

    CAS  PubMed  Google Scholar 

  199. 199.

    Song, W. J., Du, J. Z., Sun, T. M., Zhang, P. Z. & Wang, J. Gold nanoparticles capped with polyethyleneimine for enhanced siRNA delivery. Small 6, 239–246 (2010).

    CAS  PubMed  Google Scholar 

  200. 200.

    Oh, Y. K. et al. Enhanced adjuvanticity of interleukin-2 plasmid DNA administered in polyethylenimine complexes. Vaccine 21, 2837–2843 (2003).

    CAS  PubMed  Google Scholar 

  201. 201.

    Wang, C. et al. In situ formed reactive oxygen species – responsive scaffold with gemcitabine and checkpoint inhibitor for combination therapy. Sci. Transl Med. 10, 1–12 (2018). In this paper, injectable hydrogels were designed to degrade in response to reactive oxygen species in the tumour microenvironment for the sustained release of a combination chemotherapy and immunotherapy, demonstrating that hydrogels can enable high-precision control over the release kinetics of a combination of therapeutics simultaneously.

    Google Scholar 

  202. 202.

    Nathan, C. & Cunningham-Bussel, A. Beyond oxidative stress: an immunologist’s guide to reactive oxygen species. Nat. Rev. Immunol. 13, 349–361 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. 203.

    Topalian, S. L. et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32, 1020–1030 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. 204.

    Ye, Y. et al. A melanin-mediated cancer immunotherapy patch. Sci. Immunol. 2, aan5692 (2017).

    Google Scholar 

  205. 205.

    Yu, J. et al. Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery. Proc. Natl Acad. Sci. USA 112, 8260–8265 (2015).

    CAS  PubMed  Google Scholar 

  206. 206.

    Wallace, A. et al. Transforming growth factor-β receptor blockade augments the effectiveness of adoptive T cell therapy of established solid cancers. Clin. Cancer Res. 14, 3966–3974 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. 207.

    Stephan, M. T., Moon, J. J., Um, S. H., Bersthteyn, A. & Irvine, D. J. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nat. Med. 16, 1035–1041 (2010). In this paper, T cells with surface-conjugated synthetic nanoparticles loaded with adjuvant improved donor cell stimulation and tumour elimination while minimizing systemic toxicity compared with free adjuvant administered systemically.

    CAS  PubMed  PubMed Central  Google Scholar 

  208. 208.

    Stephan, M. T., Stephan, S. B., Bak, P., Chen, J. & Irvine, D. J. Synapse-directed delivery of immunomodulators using T cell-conjugated nanoparticles. Biomaterials 33, 5776–5787 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. 209.

    Huang, B. et al. Active targeting of chemotherapy to disseminated tumors using nanoparticle-carrying T cells. Sci. Transl Med. 7, 291ra94 (2015).

    PubMed  PubMed Central  Google Scholar 

  210. 210.

    Rosenberg, S. A. & Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. 211.

    Smith, T. et al. In situ programming of leukaemia-specific T cells using synthetic DNA nanocarriers. Nat. Nanotechnol. 12, 813–820 (2017). In this paper, a DNA nanoparticle platform was used to target T cells in the circulation and reprogramme them to express leukaemia-recognizing CAR genes as an alternative to ex vivo CAR T cell engineering.

    CAS  PubMed  PubMed Central  Google Scholar 

  212. 212.

    Mangraviti, A. et al. Polymeric nanoparticles for nonviral gene therapy extend brain tumor survival in vivo. ACS Nano 9, 1236–1249 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. 213.

    Smith, T. T. et al. Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors. J. Clin. Invest. 127, 2176–2191 (2017).

    PubMed  PubMed Central  Google Scholar 

  214. 214.

    Barrett, D. M., Singh, N., Porter, D. L., Grupp, S. A. & June, C. H. Chimeric antigen receptor therapy for cancer. Annu. Rev. Med. 65, 333–347 (2014).

    CAS  PubMed  Google Scholar 

  215. 215.

    Rosenberg, S. A. et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T cell transfer immunotherapy. Clin. Cancer Res. 17, 4550–4557 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. 216.

    Robbins, P. F. et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J. Clin. Oncol. 29, 917–924 (2011).

    PubMed  PubMed Central  Google Scholar 

  217. 217.

    Lamers, C. H. J. et al. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol. Ther. 21, 904–912 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. 218.

    Yaghoubi, S. et al. Noninvasive detection of therapeutic cytolytic T cells with 18F–FHBG PET in a patient with glioma. Nat. Clin. Pract. Oncol. 6, 53–58 (2009).

    CAS  PubMed  Google Scholar 

  219. 219.

    Kershaw, M. H. et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin. Cancer Res. 12, 6106–6115 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. 220.

    Rhodes, K. R. & Green, J. J. Nanoscale artificial antigen presenting cells for cancer immunotherapy. Mol. Immunol. 98, 13–18 (2018).

    CAS  PubMed  Google Scholar 

  221. 221.

    Meyer, R. A. et al. Biodegradable nanoellipsoidal artificial antigen presenting cells for antigen specific T-cell activation. Small 11, 1519–1525 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. 222.

    Kosmides, A. K. et al. Biomimetic biodegradable artificial antigen presenting cells synergize with PD-1 blockade to treat melanoma. Biomaterials 118, 16–26 (2017).

    CAS  PubMed  Google Scholar 

  223. 223.

    Day, C. P., Merlino, G. & Van Dyke, T. Preclinical mouse cancer models: a maze of opportunities and challenges. Cell 163, 39–53 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. 224.

    Mestas, J. & Hughes, C. C. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004).

    CAS  PubMed  Google Scholar 

  225. 225.

    Tao, L. & Reese, T. A. Making mouse models that reflect human immune responses. Trends Immunol. 38, 181–193 (2017).

    CAS  PubMed  Google Scholar 

  226. 226.

    Sadun, R. E. et al. Immune signatures of murine and human cancers reveal unique mechanisms of tumor escape and new targets for cancer immunotherapy. Clin. Cancer Res. 13, 4016–4025 (2007).

    CAS  PubMed  Google Scholar 

  227. 227.

    Hua, S., de Matos, M. B. C., Metselaar, J. M. & Storm, G. Current trends and challenges in the clinical translation of nanoparticulate nanomedicines: pathways for translational development and commercialization. Front. Pharmacol. 9, 1–14 (2018).

    Google Scholar 

  228. 228.

    Bulbake, U., Doppalapudi, S., Kommineni, N. & Khan, W. Liposomal formulations in clinical use: an updated review. Pharmaceutics 9, 1–33 (2017).

    Google Scholar 

  229. 229.

    Bobo, D., Robinson, K. J., Islam, J., Thurecht, K. J. & Corrie, S. R. Nanoparticle-based medicines: a review of FDA-approved materials and clinical trials to date. Pharm. Res. 33, 2373–2387 (2016).

    CAS  PubMed  Google Scholar 

  230. 230.

    Danhier, F. et al. PLGA-based nanoparticles: an overview of biomedical applications. J. Control. Release 161, 505–522 (2012).

    CAS  PubMed  Google Scholar 

  231. 231.

    Gust, J. et al. Endothelial activation and blood–brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 7, 1404–1419 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. 232.

    Ren, J. et al. A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget 8, 17002–17011 (2017).

    PubMed  PubMed Central  Google Scholar 

  233. 233.

    Singh, N., Shi, J., June, C. H. & Ruella, M. Genome-editing technologies in adoptive T cell immunotherapy for cancer. Curr. Hematol. Malig. Rep. 12, 522–529 (2017).

    PubMed  PubMed Central  Google Scholar 

  234. 234.

    Liu, H. et al. Use of angiotensin system inhibitors is associated with immune activation and longer survival in nonmetastatic pancreatic ductal adenocarcinoma. Clin. Cancer Res. 23, 5959–5969 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. 235.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01821729?term=NCT01821729&rank=1 (2017).

  236. 236.

    Chauhan, V. P. et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat. Commun. 4, 2516 (2013).

    PubMed  PubMed Central  Google Scholar 

  237. 237.

    Alvey, C. et al. SIRPA-inhibited, marrow-derived macrophages engorge, accumulate, and differentiate in antibody-targeted regression of solid tumors. Curr. Biol. 27, 2065–2077 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. 238.

    Miller, M. A. et al. Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug. Nat. Commun. 6, 8692 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. 239.

    Sharei, A. et al. Ex vivo cytosolic delivery of functional macromolecules to immune cells. PLOS ONE 10, e0118803 (2015).

    PubMed  PubMed Central  Google Scholar 

  240. 240.

    Szeto, G. L. et al. Microfluidic squeezing for intracellular antigen loading in polyclonal B cells as cellular vaccines. Sci. Rep. 5, 10276 (2015).

    PubMed  Google Scholar 

  241. 241.

    Sharei, A. et al. A vector-free microfluidic platform for intracellular delivery. Proc. Natl Acad. Sci. USA 110, 2082–2087 (2013).

    CAS  PubMed  Google Scholar 

  242. 242.

    Stewart, M. P. et al. In vitro and ex vivo strategies for intracellular delivery. Nature 538, 183–192 (2016).

    CAS  PubMed  Google Scholar 

  243. 243.

    Perica, K. et al. Magnetic field-induced t cell receptor clustering by nanoparticles enhances t cell activation and stimulates antitumor activity. ACS Nano 8, 2252–2260 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  244. 244.

    Fadel, T. R. et al. A carbon nanotube-polymer composite for T cell therapy. Nat. Nanotechnol. 9, 639–647 (2014).

    CAS  PubMed  Google Scholar 

  245. 245.

    Sunshine, J. C., Perica, K., Schneck, J. P. & Green, J. J. Particle shape dependence of CD8+ T cell activation by artificial antigen presenting cells. Biomaterials 35, 269–277 (2014).

    CAS  PubMed  Google Scholar 

  246. 246.

    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). In this paper, scaffolds containing silica microrods were coated with APC-mimetic ligands to induce T cell expansion ex vivo. This technology is five times more effective at expanding CD19 CAR T cells than a traditional ex vivo approach, providing a more efficient means of preparing T cells for immunotherapy.

    CAS  PubMed  PubMed Central  Google Scholar 

  247. 247.

    Andorko, J. I., Hess, K. L., Pineault, K. G. & Jewell, C. M. Intrinsic immunogenicity of rapidly-degradable polymers evolves during degradation. Acta Biomater. 32, 24–34 (2016).

    CAS  PubMed  Google Scholar 

  248. 248.

    Andorko, J. I., Pineault, K. G. & Jewell, C. M. Impact of molecular weight on the intrinsic immunogenic activity of poly(beta amino esters). J. Biomed. Mater. Res. A 105, 1219–1229 (2017).

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Acknowledgements

M.J.M. is supported by a Burroughs Wellcome Fund Career Award at the Scientific Interface, a US National Institutes of Health (NIH) Director’s New Innovator Award (DP2 TR002776) and a grant from the American Cancer Society (129784-IRG-16-188-38-IRG). R.S.R. is supported by an NIH T32 multidisciplinary training grant. The authors’ work is supported in part by Cancer Center Support (core) Grant P30-CA14051 from the US National Cancer Institute and a grant from the Koch Institute’s Marble Centre for Cancer Nanomedicine (to R.L.).

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R.S.R., C.H.J., R.L. and M.J.M. conceived the ideas, researched the data for the manuscript, discussed the manuscript content and wrote the manuscript. M.J.M. and R.S.R. designed the display items. All authors reviewed and edited the article before submission.

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Correspondence to Robert Langer or Michael J. Mitchell.

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R.L. receives royalties from patents (as part of Massachusetts Institute of Technology (MIT) disbursements) that MIT has licensed or holds equity or receives consulting fees from Pfizer, Translate Bio, Editas, SQZ Biotech, Capio Biosciences, Combined Therapeutics, Moderna Therapeutics, Rubius Therapeutics, Tarveda Therapeutics and Verseau Therapeutics. C.H.J. works under a research collaboration involving the University of Pennsylvania and the Novartis Institutes of Biomedical Research, Inc. C.H.J. is an inventor of intellectual property licensed by the University of Pennsylvania to Novartis. C.H.J. has sponsored research and equity from Tmunity Therapeutics. C.H.J. is a consultant for Immune Design, Viracta and Carisma.

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Glossary

Cytokine release syndrome

Rapid release of cytokines leading to adverse symptoms such as increased heartbeat, nausea and low blood pressure.

Vascular leak syndrome

Increased vascular permeability that causes fluids from capillary vessels to enter tissues, which can lead to organ damage.

Dendritic cell

A type of antigen-presenting cell whose main function is to present antigens to T cells to modulate the immune system.

Regulatory T cells

A T cell population that maintains tolerance to self-antigens and prevents autoimmune disease.

Macrophages

A type of immune cell found at sites of infection and in tumour microenvironments.

Natural killer (NK) cells

A type of lymphocyte that can bind to and kill tumour cells.

Lymphocytes

A type of white blood cell found in the lymphatic system.

CD4+ T cells

T helper cells that regulate immune responses.

CD8+ T cells

Cytotoxic T cells that kill abnormal cells.

Antigen-presenting cells

(APCs). Immune cells that present antigens to T cells to modulate immune responses.

B cell aplasia

An adverse side effect of chimeric antigen receptor T cell therapy characterized by low numbers of B cells.

Click chemistry

A type of reaction commonly used for bioconjugation of molecules to delivery systems.

Dendrimers

A type of synthetic polymer with a branch-like structure.

Patient-derived xenograft (PDX) models

Cancer models in which patient-derived tumour tissue or cells are implanted into immunocompromised mice.

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Riley, R.S., June, C.H., Langer, R. et al. Delivery technologies for cancer immunotherapy. Nat Rev Drug Discov 18, 175–196 (2019). https://doi.org/10.1038/s41573-018-0006-z

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