Research into the immunological processes implicated in cancer has yielded a basis for the range of immunotherapies that are now considered the fourth pillar of cancer treatment (alongside surgery, radiotherapy and chemotherapy). For some aggressive cancers, such as advanced non-small-cell lung carcinoma, combination immunotherapies have resulted in unprecedented treatment efficacy for responding patients, and have become frontline therapies. Individualized immunotherapy, enabled by the identification of patient-specific mutations, neoantigens and biomarkers, and facilitated by advances in genomics and proteomics, promises to broaden the responder patient population. In this Perspective, we give an overview of immunotherapies leveraging engineering approaches, including the design of biomaterials, delivery strategies and nanotechnology solutions, for the realization of individualized cancer treatments such as nanoparticle vaccines customized with neoantigens, cell therapies based on patient-derived dendritic cells and T cells, and combinations of theranostic strategies. Developments in precision cancer immunotherapy will increasingly rely on the adoption of engineering principles.
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Pardoll, D. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).
Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).
Rosenberg, J. E. et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387, 1909–1920 (2016).
Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).
Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).
Demaria, S. et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin. Cancer Res. 11, 728–734 (2005).
Vanneman, M. & Dranoff, G. Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer 12, 237–251 (2012).
Cho, H. I., Barrios, K., Lee, Y. R., Linowski, A. K. & Celis, E. BiVax: a peptide/poly-IC subunit vaccine that mimics an acute infection elicits vast and effective anti-tumor CD8 T-cell responses. Cancer Immunol. Immunother. 62, 787–799 (2013).
Duraiswamy, J., Kaluza, K. M., Freeman, G. J. & Coukos, G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 73, 3591–3603 (2013).
Belcaid, Z. et al. Focal radiation therapy combined with 4–1BB activation and CTLA-4 blockade yields long-term survival and a protective antigen-specific memory response in a murine glioma model. PLoS ONE 9, e101764 (2014).
Twyman-Saint Victor, C. et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373–377 (2015).
Chen, Q. et al. Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy. Nat. Commun. 7, 1–13 (2016).
Bethune, M. & Joglekar, A. Personalized T cell-mediated cancer immunotherapy: progress and challenges. Curr. Op. Biotechnol. 48, 142–152 (2017).
Kuai, R., Ochyl, L. J., Bahjat, K. S., Schwendeman, A. & Moon, J. J. Designer vaccine nanodiscs for personalized cancer immunotherapy. Nat. Mat. 16, 489–496 (2017).
Nam, J. et al. Chemo-photothermal therapy combination elicits anti-tumor immunity against advanced metastatic cancer. Nat. Commun. 9, 1–13 (2018).
Kugler, A. et al. Regression of human metastatic renal cell carcinoma after vaccination with tumor cell–dendritic cell hybrids. Nat. Med. 6, 332–336 (2000).
Panelli, M. C. et al. Phase 1 study in patients with metastatic melanoma of immunization with dendritic cells presenting epitopes derived from the melanoma-associated antigens MART-1 and gp100. J. Immunother. 23, 487–498 (2000).
Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).
Hu, Z., Ott, P. A. & Wu, C. J. Towards personalized, tumour-specific, therapeutic vaccines for cancer. Nat. Rev. Immunol. 18, 168–182 (2018).
Sahin, U. & Tureci, O. Personalized vaccines for cancer immunotherapy. Science 359, 1355–1360 (2018).
Castle, J. C. et al. Exploiting the Mutanome for Tumor Vaccination. Cancer Res. 72, 1081–1091 (2012).
Yadav, M. et al. Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature 515, 572–576 (2014).
Gubin, M. M. et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515, 577–581 (2014).
Kreiter, S. et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520, 692–696 (2015).
Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221 (2017).
Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017).
Keskin, D. B. et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565, 234–239 (2019).
Hilf, N. et al. Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 565, 240–245 (2019).
Bijker, M. S. et al. CD8+ CTL priming by exact peptide epitopes in incomplete Freund’s adjuvant induces a vanishing CTL response, whereas long peptides induce sustained CTL reactivity. J. Immunol. 179, 5033–5040 (2007).
Kakimi, K. et al. A phase I study of vaccination with NY‐ESO‐1f peptide mixed with Picibanil OK‐432 and Montanide ISA‐51 in patients with cancers expressing the NY‐ESO‐1 antigen. Int. J. Cancer 129, 2836–2846 (2011).
van Hall, T. & van der Burg, S. H. in Advances in Immunology Vol. 114 (ed. Melief, C.) 51–76 (Elsevier, 2012).
Hailemichael, Y. et al. Persistent antigen at vaccination sites induces tumor-specific CD8+ T cell sequestration, dysfunction and deletion. Nat. Med. 19, 465–472 (2013).
Di Stasi, A., Jimenez, A. M., Minagawa, K., Al-Obaidi, M. & Rezvani, K. Review of the results of WT1 peptide vaccination strategies for myelodysplastic syndromes and acute myeloid leukemia from nine different studies. Front. Immunol. 6, 1–6 (2015).
Blander, J. M. & Medzhitov, R. Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature 440, 808–812 (2006).
Iwasaki, A. & Medzhitov, R. Regulation of adaptive immunity by the innate immune system. Science 327, 291–295 (2010).
Fan, Y. C. & Moon, J. J. Nanoparticle drug delivery systems designed to improve cancer vaccines and immunotherapy. Vaccines 3, 662–685 (2015).
Reddy, S. T. et al. Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nat. Biotechnol. 25, 1159–1164 (2007).
Irvine, D. J., Hanson, M. C., Rakhra, K. & Tokatlian, T. Synthetic nanoparticles for vaccines and immunotherapy. Chem. Rev. 115, 11109–11146 (2015).
Shi, J., Kantoff, P. W., Wooster, R. & Farokhzad, O. C. Cancer nanomedicine: progress, challenges and opportunities. Nat. Rev. Cancer 17, 20–37 (2017).
Kuai, R., Li, D., Chen, Y. E., Moon, J. J. & Schwendeman, A. High-density lipoproteins: nature’s multifunctional nanoparticles. ACS Nano 10, 3015–3041 (2016).
Cruz, P. M., Mo, H., McConathy, W. J., Sabnis, N. & Lacko, A. G. The role of cholesterol metabolism and cholesterol transport in carcinogenesis: a review of scientific findings, relevant to future cancer therapeutics. Front. Pharmacol. 4, 1–7 (2013).
Zheng, Y. et al. Scavenger receptor B1 is a potential biomarker of human nasopharyngeal carcinoma and its growth is inhibited by HDL-mimetic nanoparticles. Theranostics 3, 477–486 (2013).
Shahzad, M. M. et al. Targeted delivery of small interfering RNA using reconstituted high-density lipoprotein nanoparticles. Neoplasia 13, 309–319 (2011).
Qian, Y. et al. Targeting dendritic cells in lymph node with an antigen peptide-based nanovaccine for cancer immunotherapy. Biomaterials 98, 171–183 (2016).
Kuai, R. et al. Subcutaneous nanodisc vaccination with neoantigens for combination cancer immunotherapy. Bioconj. Chem. 29, 771–775 (2018).
Kuai, R. et al. Dual TLR agonist nanodiscs as a strong adjuvant system for vaccines and immunotherapy. J Control Release 282, 131–139 (2018).
Irvine, D. Material aid for vaccines. Nat. Mat. 17, 472–473 (2018).
Tyagi, P. & Santos, J. L. Macromolecule nanotherapeutics: approaches and challenges. Drug Discov. Today 23, 1053–1061 (2018).
Liu, H. et al. Structure-based programming of lymph-node targeting in molecular vaccines. Nature 507, 519–522 (2014).
Zhu, G. et al. Albumin/vaccine nanocomplexes that assemble in vivo for combination cancer immunotherapy. Nat. Commun. 8, 1–15 (2017).
Dawidczyk, C. M. et al. State-of-the-art in design rules for drug delivery platforms: lessons learned from FDA-approved nanomedicines. J. Control Release 187, 133–144 (2014).
Wittrock, S., Becker, T. & Kunz, H. Synthetic vaccines of tumor-associated glycopeptide antigens by immune-compatible thioether linkage to bovine serum albumin. Angew. Chem. Int. 46, 5226–5230 (2007).
Wang, P. et al. An albumin-binding polypeptide both targets cytotoxic T lymphocyte vaccines to lymph nodes and boosts vaccine presentation by dendritic cells. Theranostics 8, 223–236 (2018).
Zhu, G. et al. Intertwining DNA-RNA nanocapsules loaded with tumor neoantigens as synergistic nanovaccines for cancer immunotherapy. Nat. Commun. 8, 1–13 (2017).
Luo, M. et al. A STING-activating nanovaccine for cancer immunotherapy. Nat. Nanotechnol. 12, 648–654 (2017).
Li, A. W. et al. A facile approach to enhance antigen response for personalized cancer vaccination. Nat. Mat. 17, 528–534 (2018).
Wegmann, F. et al. Polyethyleneimine is a potent mucosal adjuvant for viral glycoprotein antigens. Nat. Biotechnol. 30, 883–888 (2012).
Rosenberg, S. A., Yang, J. C. & Restifo, N. P. Cancer immunotherapy: moving beyond current vaccines. Nat. Med. 10, 909–915 (2004).
Kent, S. J. et al. Enhanced T-cell immunogenicity and protective efficacy of a human immunodeficiency virus type 1 vaccine regimen consisting of consecutive priming with DNA and boosting with recombinant fowlpox virus. J. Virol. 72, 10180–10188 (1998).
Rosenberg, S. A. et al. Recombinant fowlpox viruses encoding the anchor-modified gp100 melanoma antigen can generate antitumor immune responses in patients with metastatic melanoma. Clin. Cancer Res. 9, 2973–2980 (2003).
Kaufman, H. L. et al. Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma. J. Clin. Invest. 115, 1903–1912 (2005).
Rosenberg, S. A. et al. Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-1 or gp100 melanoma antigens. J. Natl Cancer Inst. 90, 1870–1872 (1998).
Parker, J. N. et al. Engineered herpes simplex virus expressing IL-12 in the treatment of experimental murine brain tumors. Proc. Natl Acad. Sci. USA 97, 2208–2213 (2000).
Markert, J. M. et al. Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM. Mol. Ther. 17, 199–207 (2008).
Varghese, S. et al. Enhanced therapeutic efficacy of IL-12, but not GM-CSF, expressing oncolytic herpes simplex virus for transgenic mouse derived prostate cancers. Cancer Gene Ther. 13, 253–265 (2005).
Joshi, B. H. et al. In situ expression of interleukin-4 (IL-4) receptors in human brain tumors and cytotoxicity of a recombinant IL-4 cytotoxin in primary glioblastoma cell cultures. Cancer Res. 61, 8058–8061 (2001).
Cheng, W.-F. et al. Enhancement of Sindbis virus self-replicating RNA vaccine potency by linkage of herpes simplex virus type 1 VP22 protein to antigen. J. Virol. 75, 2368–2376 (2001).
Herweijer, H. & Wolff, J. Progress and prospects: naked DNA gene transfer and therapy. Gene Ther. 10, 453–458 (2003).
Kawabata, K., Takakura, Y. & Hashida, M. The fate of plasmid DNA after intravenous injection in mice: involvement of scavenger receptors in its hepatic uptake. Pharm. Res. 12, 825–830 (1995).
Nomura, T. et al. Intratumoral pharmacokinetics and in vivo gene expression of naked plasmid DNA and its cationic liposome complexes after direct gene transfer. Can. Res. 57, 2681–2686 (1997).
Li, S. & Huang, L. In vivo gene transfer via intravenous administration of cationic lipid-protamine-DNA (LPD) complexes. Gene Ther. 4, 891–900 (1997).
Xu, Y. & Szoka, F. C. Jr. Mechanism of DNA release from cationic liposome/DNA complexes used in cell transfection. Biochemistry 35, 5616–5623 (1996).
Cheng, J. Y. et al. Transcutaneous immunization by lipoplex-patch based DNA vaccines is effective vaccination against Japanese encephalitis virus infection. J. Control Rel. 135, 242–249 (2009).
Gill, H. S., Soderholm, J., Prausnitz, M. R. & Sallberg, M. Cutaneous vaccination using microneedles coated with hepatitis C DNA vaccine. Gene Ther. 17, 811–814 (2010).
Rice, J., Ottensmeier, C. H. & Stevenson, F. K. DNA vaccines: precision tools for activating effective immunity against cancer. Nat. Rev. Cancer 8, 108–120 (2008).
Kutzler, M. A. & Weiner, D. B. DNA vaccines: ready for prime time? Nat. Rev. Genet. 9, 776–788 (2008).
Schlake, T., Thess, A., Fotin-Mleczek, M. & Kallen, K. J. Developing mRNA-vaccine technologies. RNA Biol. 9, 1319–1330 (2012).
Geall, A. J., Mandl, C. W. & Ulmer, J. B. RNA: the new revolution in nucleic acid vaccines. Semin. Immunol. 25, 152–159 (2013).
Deering, R. P., Kommareddy, S., Ulmer, J. B., Brito, L. A. & Geall, A. J. Nucleic acid vaccines: prospects for non-viral delivery of mRNA vaccines. Expert Opin. Drug Deliv. 11, 885–899 (2014).
Kato, H. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441, 101–105 (2006).
Thompson, A. J. & Locarnini, S. A. Toll-like receptors, RIG-I-like RNA helicases and the antiviral innate immune response. Immunol. Cell Biol. 85, 435–445 (2007).
Kreiter, S. et al. Intranodal vaccination with naked antigen-encoding RNA elicits potent prophylactic and therapeutic antitumoral immunity. Cancer Res. 70, 9031–9040 (2010).
Kranz, L. M. et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534, 396–401 (2016).
Sayour, E. J. et al. Systemic activation of antigen-presenting cells via RNA-loaded nanoparticles. Oncoimmunology 6, e1256527 (2017).
Yu, J. S. et al. Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res. 64, 4973–4979 (2004).
Kim, C.-H. et al. Enhancement of anti-tumor immunity specific to murine glioma by vaccination with tumor cell lysate-pulsed dendritic cells engineered to produce interleukin-12. Cancer Immunol. Immunother. 55, 1309–1319 (2006).
Geiger, J. D. et al. Vaccination of pediatric solid tumor patients with tumor lysate-pulsed dendritic cells can expand specific T cells and mediate tumor regression. Cancer Res. 61, 8513–8519 (2001).
Tanyi, J. L. et al. Personalized cancer vaccine effectively mobilizes antitumor T cell immunity in ovarian cancer. Sci. Transl. Med. 10, eaao5931 (2018).
Fadul, C. E. et al. Immune response in patients with newly diagnosed glioblastoma multiforme treated with intranodal autologous tumor lysate-dendritic cell vaccination after radiation chemotherapy. J. Immunother. 34, 382–389 (2011).
Schwaab, T. et al. Clinical and immunologic effects of intranodal autologous tumor lysate-dendritic cell vaccine with aldesleukin (interleukin 2) and IFN-α2a therapy in metastatic renal cell carcinoma patients. Clin. Cancer Res. 15, 4986–4992 (2009).
Carreno, B. M. et al. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science 348, 803–808 (2015).
Srinivas, M. et al. Imaging of cellular therapies. Adv. Drug Deliv. Rev. 62, 1080–1093 (2010).
Bencherif, S. A. et al. Injectable cryogel-based whole-cell cancer vaccines. Nat. Commun. 6, 7556 (2015).
Verbeke, C. S. & Mooney, D. J. Injectable, Pore-Forming Hydrogels for In Vivo Enrichment of Immature Dendritic Cells. Adv. Healthcare Mat. 4, 2677–2687 (2015).
Shih, T. Y. et al. Injectable, tough alginate cryogels as cancer vaccines. Adv. Healthcare Mat. 7, e1701469 (2018).
Théry, C., Zitvogel, L. & Amigorena, S. Exosomes: composition, biogenesis and function. Nat. Rev. Immunol. 2, 569–579 (2002).
Squadrito, M. L., Cianciaruso, C., Hansen, S. K. & De Palma, M. EVIR: chimeric receptors that enhance dendritic cell cross-dressing with tumor antigens. Nat. Methods 15, 183–186 (2018).
Pitt, J. M. et al. Dendritic cell-derived exosomes for cancer therapy. J. Clin. Invest. 126, 1224–1232 (2016).
Escudier, B. et al. Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial. J. Transl. Med. 3, 1–13 (2005).
Morse, M. A. et al. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J. Transl. Med. 3, 1–8 (2005).
Dai, S. et al. Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol. Ther. 16, 782–790 (2008).
Besse, B. et al. Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC. Oncoimmunology 5, e1071008 (2016).
van Dommelen, S. M. et al. Microvesicles and exosomes: opportunities for cell-derived membrane vesicles in drug delivery. J. Control Rel. 161, 635–644 (2012).
Johnsen, K. B. et al. A comprehensive overview of exosomes as drug delivery vehicles - endogenous nanocarriers for targeted cancer therapy. Biochim. Biophys. Acta 1846, 75–87 (2014).
Restifo, N. P., Dudley, M. E. & Rosenberg, S. A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 12, 269–281 (2012).
Rosenberg, S. A. & Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015).
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).
Tang, J., Shalabi, A. & Hubbard-Lucey, V. M. Comprehensive analysis of the clinical immuno-oncology landscape. Ann. Oncol. 29, 84–91 (2018).
Lauss, M. et al. Mutational and putative neoantigen load predict clinical benefit of adoptive T cell therapy in melanoma. Nat. Commun. 8, 1–11 (2017).
Chheda, Z. et al. Novel and shared neoantigen derived from histone 3 variant H3.3K27M mutation for glioma T cell therapy. J. Exp. Med. 215, 141–157 (2018).
Smith, T. T. et al. In situ programming of leukaemia-specific T cells using synthetic DNA nanocarriers. Nat. Nanotechnol. 12, 813–820 (2017).
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).
Fadel, T. R. et al. A carbon nanotube-polymer composite for T-cell therapy. Nat. Nanotechnol. 9, 639–647 (2014).
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).
Stephan, M., Moon, J., Um, S., Bershteyn, A. & Irvine, D. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nat. Med. 16, 1035–1041 (2010).
Huang, B. et al. Active targeting of chemotherapy to disseminated tumors using nanoparticle-carrying T cells. Sci. Transl. Med. 7, 1–21 (2015).
Zheng, Y. et al. In vivo targeting of adoptively transferred T-cells with antibody- and cytokine-conjugated liposomes. J. Cont. Rel. 172, 426–435 (2013).
Zheng, Y., Tang, L., Mabardi, L., Kumari, S. & Irvine, D. Enhancing adoptive cell therapy of cancer through targeted delivery of small-molecule immunomodulators to internalizing or noninternalizing receptors. ACS Nano 11, 3089–3100 (2017).
Smith, T. et al. Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors. J. Clin. Invest. 127, 2176–2191 (2017).
Stephan, S. et al. Biopolymer implants enhance the efficacy of adoptive T-cell therapy. Nat. Biotechnol. 33, 97–101 (2015).
Li, J. & Mooney, D. J. Designing hydrogels for controlled drug delivery. Nat. Rev. Mater. 1, 16071 (2016).
Chen, G. et al. MRI-visible polymeric vector bearing CD3 single chain antibody for gene delivery to T cells for immunosuppression. Biomaterials 30, 1962–1970 (2009).
Fan, Z., Chen, D. & Deng, C. Improving ultrasound gene transfection efficiency by controlling ultrasound excitation of microbubbles. J. Contr. Rel. 170, 401–413 (2013).
Weber-Adrian, D. et al. Gene delivery to the spinal cord using MRI-guided focused ultrasound. Gene Ther. 22, 568–577 (2015).
Chertok, B., Langer, R. & Anderson, D. G. Spatial control of gene expression by nanocarriers using heparin masking and ultrasound-targeted microbubble destruction. ACS Nano 10, 7267–7278 (2016).
Mead, B. P. et al. Targeted gene transfer to the brain via the delivery of brain-penetrating DNA nanoparticles with focused ultrasound. J. Contr. Rel. 223, 109–117 (2016).
Fan, C.-H. et al. Folate-conjugated gene-carrying microbubbles with focused ultrasound for concurrent blood-brain barrier opening and local gene delivery. Biomaterials 106, 46–57 (2016).
Ling, D. et al. Multifunctional tumor pH-sensitive self-assembled nanoparticles for bimodal imaging and treatment of resistant heterogeneous tumors. J. Am. Chem. Soc. 136, 5647–5655 (2014).
Yang, K. et al. Multimodal imaging guided photothermal therapy using functionalized graphene nanosheets anchored with magnetic nanoparticles. Adv. Mat. 24, 1868–1872 (2012).
Lee, J.-H. et al. Exchange-coupled magnetic nanoparticles for efficient heat induction. Nat. Nanotechnol. 6, 418–422 (2011).
Riedinger, A. et al. Subnanometer local temperature probing and remotely controlled drug release based on azo-functionalized iron oxide nanoparticles. Nano Lett. 13, 2399–2406 (2013).
Hayashi, K. et al. Superparamagnetic nanoparticle clusters for cancer theranostics combining magnetic resonance imaging and hyperthermia treatment. Theranostics 3, 366–376 (2013).
Dames, P. et al. Targeted delivery of magnetic aerosol droplets to the lung. Nat. Nanotechnol. 2, 495–499 (2007).
Amirfazli, A. Nanomedicine: magnetic nanoparticles hit the target. Nat. Nanotechnol. 2, 467–468 (2007).
Galanzha, E. I. et al. In vivo magnetic enrichment and multiplex photoacoustic detection of circulating tumour cells. Nat. Nanotechnol. 4, 855–860 (2009).
Shevtsov, M. A. et al. 70-kDa heat shock protein coated magnetic nanocarriers as a nanovaccine for induction of anti-tumor immune response in experimental glioma. J. Cont. Rel. 220, 329–340 (2015).
Sirsi, S. & Borden, M. Microbubble Compositions, Properties and Biomedical Applications. Bubble Sci. Eng. Technol. 1, 3–17 (2009).
Treat, L. H. et al. Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI‐guided focused ultrasound. Int. J. Cancer 121, 901–907 (2007).
Burke, C. W., Alexander, E., Timbie, K., Kilbanov, A. L. & Price, R. J. Ultrasound-activated agents comprised of 5FU-bearing nanoparticles bonded to microbubbles inhibit solid tumor growth and improve survival. Mol. Ther. 22, 321–328 (2014).
Chen, P.-Y. et al. Focused ultrasound-induced blood–brain barrier opening to enhance interleukin-12 delivery for brain tumor immunotherapy: a preclinical feasibility study. J. Transl Med. 13, 1–12 (2015).
Timbie, K. F. et al. MR image-guided delivery of cisplatin-loaded brain-penetrating nanoparticles to invasive glioma with focused ultrasound. J. Cont. Rel. 263, 120–131 (2017).
Suzuki, R. et al. A novel strategy utilizing ultrasound for antigen delivery in dendritic cell-based cancer immunotherapy. J. Cont. Rel. 133, 198–205 (2009).
Zhou, S. et al. Ultrasound-targeted microbubble destruction mediated herpes simplex virus-thymidine kinase gene treats hepatoma in mice. J. Exp. Clin. Cancer Res. 29, 1–6 (2010).
Unga, J. & Hashida, M. Ultrasound induced cancer immunotherapy. Adv. Drug Del. Rev. 72, 144–153 (2014).
Yap, J. T., Carney, J. P., Hall, N. C. & Townsend, D. W. Image‐guided cancer therapy using PET/CT. Cancer J. 10, 221–233 (2004).
Bundschuh, R. A. et al. Textural parameters of tumor heterogeneity in 18F-FDG PET/CT for therapy response assessment and prognosis in patients with locally advanced rectal cancer. J. Nucl. Med. 55, 891–897 (2014).
Hillner, B. E. et al. 18F-fluoride PET used for treatment monitoring of systemic cancer therapy: results from the National Oncologic PET Registry. J. Nucl. Med. 56, 222–228 (2015).
Connolly, R. M. et al. TBCRC 008: early change in 18F-FDG uptake on PET predicts response to preoperative systemic therapy in human epidermal growth factor receptor 2–negative primary operable breast cancer. J. Nucl. Med. 56, 31–37 (2015).
Norregaard, K. et al. 18F-FDG PET/CT-based early treatment response evaluation of nanoparticle-assisted photothermal cancer therapy. PLoS ONE 12, e0177997 (2017).
Kuai, R. et al. Elimination of established tumors with nanodisc-based combination chemoimmunotherapy. Sci. Adv. 4, eaao1736 (2018).
Nam, J., Son, S. & Moon, J. J. Adjuvant-loaded spiky gold nanoparticles for activation of innate immune cells. Cell. Mol. Bioeng. 10, 341–355 (2017).
He, C. et al. Core-shell nanoscale coordination polymers combine chemotherapy and photodynamic therapy to potentiate checkpoint blockade cancer immunotherapy. Nat. Commun. 7, 1–12 (2016).
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).
Min, Y. et al. Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy. Nat. Nanotechnol. 12, 877–882 (2017).
Demaria, S., Golden, E. B. & Formenti, S. C. Role of local radiation therapy in cancer immunotherapy. JAMA Oncol. 1, 1325–1332 (2015).
Demaria, S., Coleman, C. N. & Formenti, S. C. Radiotherapy: changing the game in immunotherapy. Trends Cancer 2, 286–294 (2016).
Reynders, K., Illidge, T., Siva, S., Chang, J. Y. & De Ruysscher, D. The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant. Cancer Treat. Rev. 41, 503–510 (2015).
Barker, C. A. & Postow, M. A. Combinations of radiation therapy and immunotherapy for melanoma: a review of clinical outcomes. Int. J. Radiat. Oncol. Biol. Phys. 88, 986–997 (2014).
Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
Gubin, M. M., Artyomov, M. N., Mardis, E. R. & Schreiber, R. D. Tumor neoantigens: building a framework for personalized cancer immunotherapy. J. Clin. Invest. 125, 3413–3421 (2015).
Snyder, A. & Chan, T. A. Immunogenic peptide discovery in cancer genomes. Curr. Opin. Genet. Dev. 30, 7–16 (2015).
Gros, A. et al. Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat. Med. 22, 433–438 (2016).
Adalsteinsson, V. A. et al. Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors. Nat. Commun. 8, 1–13 (2017).
Bhatia, S. N. & Ingber, D. E. Microfluidic organs-on-chips. Nat. Biotechnol. 32, 760–772 (2014).
Michot, J. M. et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur. J. Cancer 54, 139–148 (2016).
Shestopalov, I., Tice, J. D. & Ismagilov, R. F. Multi-step synthesis of nanoparticles performed on millisecond time scale in a microfluidic droplet-based system. Lab Chip 4, 316–321 (2004).
Jahn, A., Vreeland, W. N., DeVoe, D. L., Locascio, L. E. & Gaitan, M. Microfluidic directed formation of liposomes of controlled size. Langmuir 23, 6289–6293 (2007).
Valencia, P. M., Farokhzad, O. C., Karnik, R. & Langer, R. Microfluidic technologies for accelerating the clinical translation of nanoparticles. Nat. Nanotechnol. 7, 623–629 (2012).
Finn, O. J. The dawn of vaccines for cancer prevention. Nat. Rev. Immunol. 18, 183–194 (2018).
Bonadona, V. et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 305, 2304–2310 (2011).
von Knebel Doeberitz, M. & Kloor, M. Towards a vaccine to prevent cancer in Lynch syndrome patients. Fam. Cancer 12, 307–312 (2013).
Nam, J. et al. Cancer nanomedicine for combination cancer immunotherapy. Nat. Rev. Mat. 4, 398–414 (2019).
This work was supported in part by NIH (grant no. R01EB022563, R01CA210273, R01CA223804, R01AI127070, R21NS091555, R01HL134569, U01CA210152, R37NS094804, RO1NS105556, R21NS107894, RO1NS096756, UO1CA224160), MTRAC for Life Sciences Hub, UM Forbes Institute for Cancer Discovery Pilot Grant and Emerald Foundation. J.J.M. is a Young Investigator supported by the Melanoma Research Alliance (grant no. 348774), DoD/CDMRP Peer Reviewed Cancer Research Program (grant no. W81XWH-16-1-0369), and NSF CAREER Award (grant no. 1553831). L.S. acknowledges financial support from the UM Pharmacological Sciences Training Program (PSTP) (grant no. GM007767 from NIGMS). K.S.P. acknowledges financial support from the UM TEAM Training Program (grant no. DE007057 from NIDCR). Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defence.
A patent application for the nanodisc vaccines has been filed, with J.J.M. and A.S. as inventors, and J.J.M. and A.S. as co-founders of EVOQ Therapeutics, LLC., which develops the technology.
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Scheetz, L., Park, K.S., Li, Q. et al. Engineering patient-specific cancer immunotherapies. Nat Biomed Eng 3, 768–782 (2019) doi:10.1038/s41551-019-0436-x