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Enhancing cancer immunotherapy with nanomedicine

Abstract

Therapeutic targeting of the immune system in cancer is now a clinical reality and marked successes have been achieved, most notably through the use of checkpoint blockade antibodies and chimeric antigen receptor T cell therapy. However, efforts to develop new immunotherapy agents or combination treatments to increase the proportion of patients who benefit have met with challenges of limited efficacy and/or significant toxicity. Nanomedicines — therapeutics composed of or formulated in carrier materials typically smaller than 100 nm — were originally developed to increase the uptake of chemotherapy agents by tumours and to reduce their off-target toxicity. Here, we discuss how nanomedicine-based treatment strategies are well suited to immunotherapy on the basis of nanomaterials’ ability to direct immunomodulators to tumours and lymphoid organs, to alter the way biologics engage with target immune cells and to accumulate in myeloid cells in tumours and systemic compartments. We also discuss early efforts towards clinical translation of nanomedicine-based immunotherapy.

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Fig. 1: Nanomedicines allow unique modes of action in immunotherapy.
Fig. 2: Nanomedicines improve tumour retention and lymph node trafficking.
Fig. 3: Systemic targeting of tumours by intravenously administered nanomedicines.
Fig. 4: Enhancing cellular immunity of cancer.

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References

  1. Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Gettinger, S. N. et al. Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J. Clin. Oncol. 33, 2004–2012 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lebbe, C. et al. Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies. Ann. Oncol. 25, 2277–2284 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Postow, M. A., Sidlow, R. & Hellmann, M. D. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378, 158–168 (2018).

    Article  CAS  PubMed  Google Scholar 

  6. Gangadhar, T. C. & Vonderheide, R. H. Mitigating the toxic effects of anticancer immunotherapy. Nat. Rev. Clin. Oncol. 11, 91–99 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Bommareddy, P. K., Shettigar, M. & Kaufman, H. L. Integrating oncolytic viruses in combination cancer immunotherapy. Nat. Rev. Immunol. 18, 498–513 (2018).

    Article  CAS  PubMed  Google Scholar 

  8. Neri, D. Antibody–cytokine fusions: versatile products for the modulation of anticancer immunity. Cancer Immunol. Res. 7, 348–354 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kureshi, R., Bahri, M. & Spangler, J. B. Reprogramming immune proteins as therapeutics using molecular engineering. Curr. Opin. Chem. Eng. 19, 27–34 (2018).

    Article  Google Scholar 

  10. Lebre, F., Hearnden, C. H. & Lavelle, E. C. Modulation of immune responses by particulate materials. Adv. Mater. 28, 5525–5541 (2016).

    Article  CAS  PubMed  Google Scholar 

  11. Smith, J. D., Morton, L. D. & Ulery, B. D. Nanoparticles as synthetic vaccines. Curr. Opin. Biotechnol. 34, 217–224 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Kelly, H. G., Kent, S. J. & Wheatley, A. K. Immunological basis for enhanced immunity of nanoparticle vaccines. Expert Rev. Vaccines 18, 269–280 (2019).

    Article  CAS  PubMed  Google Scholar 

  13. Bachmann, M. F. & Jennings, G. T. Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. Nat. Rev. Immunol. 10, 787–796 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Krysko, D. V. et al. Immunogenic cell death and DAMPs in cancer therapy. Nat. Rev. Cancer 12, 860 (2012).

    Article  CAS  PubMed  Google Scholar 

  15. Duan, X., Chan, C. & Lin, W. Nanoparticle-mediated immunogenic cell death enables and potentiates cancer immunotherapy. Angew. Chem. Int. Ed. 58, 670–680 (2019).

    Article  CAS  Google Scholar 

  16. Rios-Doria, J. et al. Doxil synergizes with cancer immunotherapies to enhance antitumor responses in syngeneic mouse models. Neoplasia 17, 661–670 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kuai, R. et al. Elimination of established tumors with nanodisc-based combination chemoimmunotherapy. Sci. Adv. 4, eaao1736 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Walle, T. et al. Radiation effects on antitumor immune responses: current perspectives and challenges. Ther. Adv. Med. Oncol. 10, 1–27 (2018).

    Article  CAS  Google Scholar 

  19. Vacchelli, E. et al. Trial watch: immunotherapy plus radiation therapy for oncological indications. Oncoimmunology 5, e1214790 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Li, T. & Chen, Z. J. The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer. J. Exp. Med. 215, 1287–1299 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Vanpouille-Box, C. et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 8, 15618 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Liang, H. et al. Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nat. Commun. 8, 1736 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Arina, A. et al. Tumor-reprogrammed resident T cells resist radiation to control tumors. Nat. Commun. 10, 3959 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Min, Y. et al. Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy. Nat. Nanotechnol. 12, 877–882 (2017). This article demonstrates a new mechanism of action for nanoparticles in augmenting in situ vaccination by capturing antigens released from tumour cells during radiotherapy and promoting uptake by antigen-presenting cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Rancoule, C. et al. Nanoparticles in radiation oncology: from bench-side to bedside. Cancer Lett. 375, 256–262 (2016).

    Article  CAS  PubMed  Google Scholar 

  26. Bonvalot, S. et al. NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial. Lancet Oncol. 20, 1148–1159 (2019). A randomized clinical trial demonstrating the use of inorganic nanoparticles in potentiating radiotherapy in patients with sarcoma.

    Article  CAS  PubMed  Google Scholar 

  27. Marill, J., Mohamed Anesary, N. & Paris, S. DNA damage enhancement by radiotherapy-activated hafnium oxide nanoparticles improves cGAS-STING pathway activation in human colorectal cancer cells. Radiother. Oncol. 141, 262–266 (2019).

    Article  CAS  PubMed  Google Scholar 

  28. Ni, K. et al. Nanoscale metal-organic frameworks enhance radiotherapy to potentiate checkpoint blockade immunotherapy. Nat. Commun. 9, 2351 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Lu, K. et al. Low-dose X-ray radiotherapy-radiodynamic therapy via nanoscale metal-organic frameworks enhances checkpoint blockade immunotherapy. Nat. Biomed. Eng. 2, 600–610 (2018).

    Article  CAS  PubMed  Google Scholar 

  30. Toraya-Brown, S. et al. Local hyperthermia treatment of tumors induces CD8+ T cell-mediated resistance against distal and secondary tumors. Nanomedicine 10, 1273–1285 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Yanase, M. et al. Antitumor immunity induction by intracellular hyperthermia using magnetite cationic liposomes. Jpn. J. Cancer Res. 89, 775–782 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hoopes, P. J. et al. Treatment of canine oral melanoma with nanotechnology-based immunotherapy and radiation. Mol. Pharm. 15, 3717–3722 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chen, Y. et al. An immunostimulatory dual-functional nanocarrier that improves cancer immunochemotherapy. Nat. Commun. 7, 13443 (2016).

    Article  CAS  PubMed  Google Scholar 

  34. Park, J. et al. Combination delivery of TGF-beta inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy. Nat. Mater. 11, 895–905 (2012). This work demonstrates an elegant strategy to co-deliver small-molecule drugs (inhibitor of transforming growth factor-β) and protein drugs (IL-2) to tumours using nanoparticles.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Duan, X. et al. Immunostimulatory nanomedicines synergize with checkpoint blockade immunotherapy to eradicate colorectal tumors. Nat. Commun. 10, 1899 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Duan, X. et al. Photodynamic therapy mediated by nontoxic core–shell nanoparticles synergizes with immune checkpoint blockade to elicit antitumor immunity and antimetastatic effect on breast cancer. J. Am. Chem. Soc. 138, 16686–16695 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. He, C. et al. Core-shell nanoscale coordination polymers combine chemotherapy and photodynamic therapy to potentiate checkpoint blockade cancer immunotherapy. Nat. Commun. 7, 12499 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kwong, B., Gai, S. A., Elkhader, J., Wittrup, K. D. & Irvine, D. J. Localized immunotherapy via liposome-anchored anti-CD137 + IL-2 prevents lethal toxicity and elicits local and systemic antitumor immunity. Cancer Res. 73, 1547–1558 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kosmides, A. K., Necochea, K., Hickey, J. W. & Schneck, J. P. Separating T cell targeting components onto magnetically clustered nanoparticles boosts activation. Nano Lett. 18, 1916–1924 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mi, Y. et al. A dual immunotherapy nanoparticle improves T-cell activation and cancer immunotherapy. Adv. Mater. 30, 1706098 (2018).

    Article  CAS  Google Scholar 

  41. Mitchell, M. J., Wayne, E., 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). This article demonstrates the use of liposomal particles to ‘present’ TRAIL from the surfaces of circulating leukocytes, promoting killing of circulating tumour cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jyotsana, N., Zhang, Z., Himmel, L. E., Yu, F. & King, M. R. Minimal dosing of leukocyte targeting TRAIL decreases triple-negative breast cancer metastasis following tumor resection. Sci. Adv. 5, eaaw4197 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Nair, P. M. et al. Enhancing the antitumor efficacy of a cell-surface death ligand by covalent membrane display. Proc. Natl Acad. Sci. USA 112, 5679–5684 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yuan, H. et al. Multivalent bi-specific nanobioconjugate engager for targeted cancer immunotherapy. Nat. Nanotechnol. 12, 763 (2017).

    Article  CAS  PubMed  Google Scholar 

  45. Kulkarni, A. et al. A designer self-assembled supramolecule amplifies macrophage immune responses against aggressive cancer. Nat. Biomed. Eng. 2, 589–599 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Shae, D. et al. Endosomolytic polymersomes increase the activity of cyclic dinucleotide STING agonists to enhance cancer immunotherapy. Nat. Nanotechnol. 14, 269–278 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Cheng, N. et al. A nanoparticle-incorporated STING activator enhances antitumor immunity in PD-L1–insensitive models of triple-negative breast cancer. JCI Insight 3, e120638 (2018).

    Article  PubMed Central  Google Scholar 

  48. Luo, M. et al. A STING-activating nanovaccine for cancer immunotherapy. Nat. Nanotechnol. 12, 648–654 (2017). The first demonstration of a synthetic polymer particle that appears to directly interact with STING to promote interferon production and T cell priming.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Guan, C. et al. RNA-based immunostimulatory liposomal spherical nucleic acids as potent TLR7/8 modulators. Small 14, e1803284 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Radovic-Moreno, A. F. et al. Immunomodulatory spherical nucleic acids. Proc. Natl Acad. Sci. USA 112, 3892–3897 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Pastor, F. et al. An RNA toolbox for cancer immunotherapy. Nat. Rev. Drug Discov. 17, 751–767 (2018).

    Article  CAS  PubMed  Google Scholar 

  52. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Hewitt, S. L. et al. Durable anticancer immunity from intratumoral administration of IL-23, IL-36gamma, and OX40L mRNAs. Sci. Transl Med. 11, eaat9143 (2019). This work demonstrates the use of in vitro screening to define candidate immunotherapy cues that would exert synergy in priming antitumour immunity, and then delivery of these cues to tumours using lipid nanoparticles carrying mRNA encoding the target genes.

    Article  CAS  PubMed  Google Scholar 

  54. Rothschilds, A. M. & Wittrup, K. D. What, why, where, and when: bringing timing to immuno-oncology. Trends Immunol. 40, 12–21 (2019).

    Article  CAS  PubMed  Google Scholar 

  55. Shimizu, T. et al. Nanogel DDS enables sustained release of IL-12 for tumor immunotherapy. Biochem. Biophys. Res. Commun. 367, 330–335 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Chu, H., Zhao, J., Mi, Y., Di, Z. & Li, L. NIR-light-mediated spatially selective triggering of anti-tumor immunity via upconversion nanoparticle-based immunodevices. Nat. Commun. 10, 2839 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Aznar, M. A. et al. Intratumoral delivery of immunotherapy-act locally, think globally. J. Immunol. 198, 31–39 (2017).

    Article  CAS  PubMed  Google Scholar 

  58. Marabelle, A., Kohrt, H., Caux, C. & Levy, R. Intratumoral immunization: a new paradigm for cancer therapy. Clin. Cancer Res. 20, 1747–1756 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Marabelle, A. et al. Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT). Ann. Oncol. 29, 2163–2174 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hammerich, L. et al. Systemic clinical tumor regressions and potentiation of PD1 blockade with in situ vaccination. Nat. Med. 25, 814–824 (2019).

    Article  CAS  PubMed  Google Scholar 

  61. Formenti, S. C. et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat. Med. 24, 1845–1851 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ray, A. et al. A phase I study of intratumoral ipilimumab and interleukin-2 in patients with advanced melanoma. Oncotarget 7, 64390–64399 (2016).

    PubMed  PubMed Central  Google Scholar 

  63. Twumasi-Boateng, K., Pettigrew, J. L., Kwok, Y. Y. E., Bell, J. C. & Nelson, B. H. Oncolytic viruses as engineering platforms for combination immunotherapy. Nat. Rev. Cancer 18, 419–432 (2018).

    Article  CAS  PubMed  Google Scholar 

  64. Biot, C. et al. Preexisting BCG-specific T cells improve intravesical immunotherapy for bladder cancer. Sci. Transl Med. 4, 137ra172 (2012).

    Article  CAS  Google Scholar 

  65. van Herpen, C. M. L. et al. Intratumoral rhIL-12 administration in head and neck squamous cell carcinoma patients induces B cell activation. Int. J. Cancer 123, 2354–2361 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. Hanes, J. et al. Controlled local delivery of interleukin-2 by biodegradable polymers protects animals from experimental brain tumors and liver tumors. Pharm. Res. 18, 899–906 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Hori, Y., Stern, P. J., Hynes, R. O. & Irvine, D. J. Engulfing tumors with synthetic extracellular matrices for cancer immunotherapy. Biomaterials 30, 6757–6767 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kwong, B., Liu, H. & Irvine, D. J. Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy. Biomaterials 32, 5134–5147 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Pluen, A. et al. Role of tumor-host interactions in interstitial diffusion of macromolecules: cranial vs. subcutaneous tumors. Proc. Natl Acad. Sci. USA 98, 4628–4633 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Goodman, T. T., Olive, P. L. & Pun, S. H. Increased nanoparticle penetration in collagenase-treated multicellular spheroids. Int. J. Nanomed. 2, 265–274 (2007).

    Article  CAS  Google Scholar 

  71. Perrault, S. D., Walkey, C., Jennings, T., Fischer, H. C. & Chan, W. C. Mediating tumor targeting efficiency of nanoparticles through design. Nano Lett. 9, 1909–1915 (2009).

    Article  CAS  PubMed  Google Scholar 

  72. Popovic, Z. et al. A nanoparticle size series for in vivo fluorescence imaging. Angew. Chem. Int. Ed. 49, 8649–8652 (2010).

    Article  CAS  Google Scholar 

  73. Lizotte, P. H. et al. In situ vaccination with cowpea mosaic virus nanoparticles suppresses metastatic cancer. Nat. Nanotechnol. 11, 295–303 (2016).

    Article  CAS  PubMed  Google Scholar 

  74. Chen, Q. et al. In situ sprayed bioresponsive immunotherapeutic gel for post-surgical cancer treatment. Nat. Nanotechnol. 14, 89–97 (2019).

    Article  CAS  PubMed  Google Scholar 

  75. Jeanbart, L. et al. Enhancing efficacy of anticancer vaccines by targeted delivery to tumor-draining lymph nodes. Cancer Immunol. Res. 2, 436–447 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Munn, D. H. & Mellor, A. L. The tumor-draining lymph node as an immune-privileged site. Immunol. Rev. 213, 146–158 (2006).

    Article  PubMed  Google Scholar 

  77. Zhou, X. et al. Precise spatiotemporal interruption of regulatory T-cell-mediated CD8+ T-cell suppression leads to tumor immunity. Cancer Res. 79, 585–597 (2019).

    Article  CAS  PubMed  Google Scholar 

  78. Schudel, A., Francis, D. M. & Thomas, S. N. Material design for lymph node drug delivery. Nat. Rev. Mater. 4, 415–428 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Thomas, S. N., Vokali, E., Lund, A. W., Hubbell, J. A. & Swartz, M. A. Targeting the tumor-draining lymph node with adjuvanted nanoparticles reshapes the anti-tumor immune response. Biomaterials 35, 814–824 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Charych, D. H. et al. NKTR-214, an engineered cytokine with biased IL2 receptor binding, increased tumor exposure, and marked efficacy in mouse tumor models. Clin. Cancer Res. 22, 680–690 (2016). Preclinical studies demonstrating the efficacy of an IL-2–polymer prodrug that alters binding of the cytokine to target receptors and promotes selective stimulation in tumours.

    Article  CAS  PubMed  Google Scholar 

  82. Charych, D. et al. Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy. PLoS One 12, e0179431 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Bentebibel, S.-E. et al. A first-in-human study and biomarker analysis of NKTR-214, a novel IL2Rβγ-biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov. 9, 711–721 (2019).

    Article  PubMed  Google Scholar 

  84. Nakamura, T. et al. Liposomes loaded with a STING pathway ligand, cyclic di-GMP, enhance cancer immunotherapy against metastatic melanoma. J. Control. Release 216, 149–157 (2015).

    Article  CAS  PubMed  Google Scholar 

  85. Torres Andón, F. & Alonso, M. J. Nanomedicine and cancer immunotherapy – targeting immunosuppressive cells. J. Drug Target. 23, 656–671 (2015).

    Article  CAS  PubMed  Google Scholar 

  86. Zhang, F. et al. Uniform brain tumor distribution and tumor associated macrophage targeting of systemically administered dendrimers. Biomaterials 52, 507–516 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kim, H. Y. et al. Quantitative imaging of tumor-associated macrophages and their response to therapy using 64Cu-labeled macrin. ACS Nano 12, 12015–12029 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Miller, M. A. et al. Radiation therapy primes tumors for nanotherapeutic delivery via macrophage-mediated vascular bursts. Sci. Transl Med. 9, eaal0225 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Turk, M. J., Waters, D. J. & Low, P. S. Folate-conjugated liposomes preferentially target macrophages associated with ovarian carcinoma. Cancer Lett. 213, 165–172 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Jeanbart, L., Kourtis, I. C., van der Vlies, A. J., Swartz, M. A. & Hubbell, J. A. 6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice. Cancer Immunol. Immun. 64, 1–14 (2015).

    Article  CAS  Google Scholar 

  92. Kourtis, I. C. et al. Peripherally administered nanoparticles target monocytic myeloid cells, secondary lymphoid organs and tumors in mice. PLoS One 8, e61646 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Sasso, M. S. et al. Low dose gemcitabine-loaded lipid nanocapsules target monocytic myeloid-derived suppressor cells and potentiate cancer immunotherapy. Biomaterials 96, 47–62 (2016).

    Article  CAS  PubMed  Google Scholar 

  94. Jahchan, N. S. et al. Tuning the tumor myeloid microenvironment to fight cancer. Front. Immunol. 10, 1611 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Rodell, C. B. et al. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy. Nat. Biomed. Eng. 2, 578–588 (2018). This article demonstrates how preferential nanoparticle accumulation in TAMs can be exploited to reprogramme this immunosuppressive cell population in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Zilio, S. et al. 4PD Functionalized dendrimers: a flexible tool for in vivo gene silencing of tumor-educated myeloid cells. J. Immunol. 198, 4166–4177 (2017).

    Article  CAS  PubMed  Google Scholar 

  97. Qian, Y. et al. Molecular-targeted immunotherapeutic strategy for melanoma via dual-targeting nanoparticles delivering small interfering RNA to tumor-associated macrophages. ACS Nano 11, 9536–9549 (2017).

    Article  CAS  PubMed  Google Scholar 

  98. Parayath, N. N., Parikh, A. & Amiji, M. M. Repolarization of tumor-associated macrophages in a genetically engineered nonsmall cell lung cancer model by intraperitoneal administration of hyaluronic acid-based nanoparticles encapsulating microRNA-125b. Nano Lett. 18, 3571–3579 (2018).

    Article  CAS  PubMed  Google Scholar 

  99. Zanganeh, S. et al. Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nat. Nanotechnol. 11, 986–994 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ledo, A. M. et al. Co-delivery of RNAi and chemokine by polyarginine nanocapsules enables the modulation of myeloid-derived suppressor cells. J. Control. Release 295, 60–73 (2019).

    Article  CAS  PubMed  Google Scholar 

  101. Turley, S. J., Cremasco, V. & Astarita, J. L. Immunological hallmarks of stromal cells in the tumour microenvironment. Nat. Rev. Immunol. 15, 669–682 (2015).

    Article  CAS  PubMed  Google Scholar 

  102. Chauhan, V. P. et al. Reprogramming the microenvironment with tumor-selective angiotensin blockers enhances cancer immunotherapy. Proc. Natl Acad. Sci. USA 116, 10674–10680 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Hoang, B. et al. Docetaxel-carboxymethylcellulose nanoparticles target cells via a SPARC and albumin dependent mechanism. Biomaterials 59, 66–76 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Ernsting, M. J. et al. Targeting of metastasis-promoting tumor-associated fibroblasts and modulation of pancreatic tumor-associated stroma with a carboxymethylcellulose-docetaxel nanoparticle. J. Control. Release 206, 122–130 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Murakami, M. et al. Docetaxel conjugate nanoparticles that target alpha-smooth muscle actin-expressing stromal cells suppress breast cancer metastasis. Cancer Res. 73, 4862–4871 (2013).

    Article  CAS  PubMed  Google Scholar 

  106. June, C. H. & Sadelain, M. Chimeric antigen receptor therapy. N. Engl. J. Med. 379, 64–73 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Yee, C. Adoptive T cell therapy: points to consider. Curr. Opin. Immunol. 51, 197–203 (2018).

    Article  CAS  PubMed  Google Scholar 

  109. Hsu, C. et al. Cytokine-independent growth and clonal expansion of a primary human CD8+ T-cell clone following retroviral transduction with the IL-15 gene. Blood 109, 5168–5177 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kerkar, S. P. et al. Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts. Cancer Res. 70, 6725–6734 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zhang, L. et al. Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. Clin. Cancer Res. 21, 2278–2288 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Stephan, M. T. & Irvine, D. J. Enhancing cell therapies from the outside in: cell surface engineering using synthetic nanomaterials. Nano Today 6, 309–325 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Stephan, M. T., Moon, J. J., Um, S. H., Bershteyn, A. & Irvine, D. J. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nat. Med. 16, 1035–1041 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Xie, Y. Q. et al. Redox-responsive interleukin-2 nanogel specifically and safely promotes the proliferation and memory precursor differentiation of tumor-reactive T-cells. Biomater. Sci. 7, 1345–1357 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Tang, L. et al. Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery. Nat. Biotechnol. 36, 707–716 (2018). This article shows how TCR signalling-mediated changes in cell surface biochemistry can be used as a trigger to link drug delivery to T cell activation in ACT.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Siriwon, N. et al. CAR-T Cells surface-engineered with drug-encapsulated nanoparticles can ameliorate intratumoral T-cell hypofunction. Cancer Immunol. Res. 6, 812–824 (2018).

    Article  CAS  PubMed  Google Scholar 

  117. Zheng, Y., Tang, L., Mabardi, L., Kumari, S. & Irvine, D. J. Enhancing adoptive cell therapy of cancer through targeted delivery of small-molecule immunomodulators to internalizing or noninternalizing receptors. ACS Nano 11, 3089–3100 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Huppa, J. B. & Davis, M. M. T-cell-antigen recognition and the immunological synapse. Nat. Rev. Immunol. 3, 973–983 (2003).

    Article  CAS  PubMed  Google Scholar 

  120. Huang, B. et al. Active targeting of chemotherapy to disseminated tumors using nanoparticle-carrying T cells. Sci. Transl Med. 7, 291ra294 (2015).

    Google Scholar 

  121. Zheng, Y. et al. In vivo targeting of adoptively transferred T-cells with antibody- and cytokine-conjugated liposomes. J. Control. Release 172, 426–435 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Schmid, D. et al. T cell-targeting nanoparticles focus delivery of immunotherapy to improve antitumor immunity. Nat. Commun. 8, 1747 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zhu, G. et al. Albumin/vaccine nanocomplexes that assemble in vivo for combination cancer immunotherapy. Nat. Commun. 8, 1954 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Ma, L. et al. Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor. Science 365, 162–168 (2019). Demonstration of an approach to deliver CAR T cell ligands to the surface of antigen-presenting cells in lymph nodes, allowing CAR T cell boosting in the native lymph node microenvironment.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 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).

    Article  CAS  PubMed  Google Scholar 

  127. Moffett, H. F. et al. Hit-and-run programming of therapeutic cytoreagents using mRNA nanocarriers. Nat. Commun. 8, 389 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Smith, T. T. et al. In situ programming of leukaemia-specific T cells using synthetic DNA nanocarriers. Nat. Nanotechnol. 12, 813–820 (2017). The first demonstration of the use of nanoparticles for direct gene delivery to generate CAR T cells in vivo in a preclinical mouse model.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Kranz, L. M. et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534, 396–401 (2016).

    Article  CAS  PubMed  Google Scholar 

  130. Netea, M. G. et al. Trained immunity: a program of innate immune memory in health and disease. Science 352, aaf1098 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Kleinnijenhuis, J. et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc. Natl Acad. Sci. USA 109, 17537–17542 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Quintin, J. et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 12, 223–232 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Mulder, W. J. M., Ochando, J., Joosten, L. A. B., Fayad, Z. A. & Netea, M. G. Therapeutic targeting of trained immunity. Nat. Rev. Drug Discov. 18, 553–566 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Freitas, R. A. Nanomedicine, Volume I: Basic Capabilities (Landes Bioscience, 1999).

  135. Shi, J., Kantoff, P. W., Wooster, R. & Farokhzad, O. C. Cancer nanomedicine: progress, challenges and opportunities. Nat. Rev. Cancer 17, 20–37 (2017).

    Article  CAS  PubMed  Google Scholar 

  136. 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 Deliv. Rev. 65, 71–79 (2013).

    Article  CAS  PubMed  Google Scholar 

  137. Chauhan, V. P. & Jain, R. K. Strategies for advancing cancer nanomedicine. Nat. Mater. 12, 958 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. 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).

    Article  CAS  PubMed  Google Scholar 

  139. Wilhelm, S. et al. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 1, 16014 (2016).

    Article  CAS  Google Scholar 

  140. Golombek, S. K. et al. Tumor targeting via EPR: strategies to enhance patient responses. Adv. Drug Deliv. Rev. 130, 17–38 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Liu, J. et al. Assessing immune-related adverse events of efficacious combination immunotherapies in preclinical models of cancer. Cancer Res. 76, 5288–5301 (2016).

    Article  CAS  PubMed  Google Scholar 

  142. Wang, Y. et al. A nanoparticle-based strategy for the imaging of a broad range of tumours by nonlinear amplification of microenvironment signals. Nat. Mater. 13, 204–212 (2014).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by the US National Institutes of Health (awards CA235375, EB022433 and CA206218), the Mayo Clinic–Koch Institute Cancer Solutions Team Grant funding, the Marble Center for Nanomedicine and the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University. D.J.I. is an investigator of the Howard Hughes Medical Institute.

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Correspondence to Darrell J. Irvine.

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D.J.I. and E.L.D. are co-inventors on patents related to nanoparticle delivery of innate immune stimulators assigned to Massachusetts Institute of Technology (MIT). D.J.I. is an inventor on patents related to nanomedicine-based immunotherapy assigned to MIT that have been licensed to Torque Therapeutics, Elicio Therapeutics and Strand Therapeutics, of which D.J.I. is a co-founder.

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Nature Reviews Immunology thanks B. Kim and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Cyclic GMP–AMP synthase–stimulator of interferon genes pathway

(cGAS–STING pathway). An intracellular signalling pathway that responds to cytosolic double-stranded DNA through the sensor enzyme cGAS to produce the second messenger cyclic GMP–AMP, which subsequently activates STING and can stimulate cells to produce type I interferons and other cytokines.

Abscopal response

Immunological response to radiotherapy or other localized therapies whereby the treatment of a malignant lesion results in the regression or stabilization of distant, non-treated lesions.

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Irvine, D.J., Dane, E.L. Enhancing cancer immunotherapy with nanomedicine. Nat Rev Immunol 20, 321–334 (2020). https://doi.org/10.1038/s41577-019-0269-6

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