Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Cancer immunotherapies revisited: state of the art of conventional treatments and next-generation nanomedicines

Cancer Gene Therapy volume 28, pages 935–946 (2021)Cite this article

Subjects

Abstract

Nowadays, the landscape of cancer treatments has broadened thanks to the clinical application of immunotherapeutics. After decades of failures, cancer immunotherapy represents an exciting alternative for those patients suffering from a wide variety of cancers, especially for those skin cancers, such as the early stages of melanoma. However, those cancers affecting internal organs still face a long way to success, because of the poor biodistribution of immunotherapies. Here, nanomedicine appears as a hopeful strategy to modulate the biodistribution aiming at target organ accumulation. In this way, efficacy will be improved, while reducing the side effects at the same time. In this review, we aim to highlight the most promising cancer immunotherapeutic strategies. From monoclonal antibodies and their traditional use as targeted therapies to their current use as immune checkpoint inhibitors; as well as adoptive cell transfer therapies; oncolytic viruses, and therapeutic cancer vaccination. Then, we aim to discuss the important role of nanomedicine to improve the performance of these immunotherapeutic tools to finally review the already marketed nanomedicine-based cancer immunotherapies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Antibody-Drug Conjugate.
Fig. 2: Adoptive cell therapies.
Fig. 3: Tumor infiltrating therapies.
Fig. 4: General working principle of mRNA vaccine nanoformulation.

Similar content being viewed by others

References

  1. GCO. Global Cancer Observatory. 2020. p. 1–2.

  2. Abbas Z, Rehman S. An overview of cancer treatment modalities. In: Shahzad HN, editor. Neoplasm; 2018.

  3. Morrissey K, Yuraszeck T, Li CC, Zhang Y, Kasichayanula S. Immunotherapy and novel combinations in oncology: current landscape, challenges, and opportunities. Clin Transl Sci. 2016;9:89–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Coates A, Abraham S, Kaye SB, Sowerbutts T, Frewin C, Fox RM, et al. On the receiving end-patient perception of the side-effects of cancer chemotherapy. Eur J Cancer Clin Oncol. 1983;19:203–8.

    Article  CAS  PubMed  Google Scholar 

  5. Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: the beginning of the end of cancer? BMC Med. 2016;14:1–18.

    Article  CAS  Google Scholar 

  6. Weiner LM, Murray JC, Shuptrine CW. Antibody-based immunotherapy of cancer. Cell. 2012;148:1081–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Topalian SL, Weiner GJ, Pardoll DM. Cancer immunotherapy comes of age. J Clin Oncol. 2011;29:4828–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

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

    Article  PubMed  PubMed Central  Google Scholar 

  10. Howard KA, Vorup-jensen T, Peer D. Nanomedicine. Springer; 2016.

  11. Hare JI, Lammers T, Ashford MB, Puri S, Storm G, Barry ST. Challenges and strategies in anti-cancer nanomedicine development: an industry perspective. Adv Drug Deliv Rev. 2017;108:25–38.

    Article  CAS  PubMed  Google Scholar 

  12. Bawa R, Audette GF, Rubinstein I. Clinical nanomedicine. Vol. 1; 2016.

  13. Wicki A, Witzigmann D, Balasubramanian V, Huwyler J. Nanomedicine in cancer therapy: Challenges, opportunities, and clinical applications. J Control Release. 2015;200:138–57.

    Article  CAS  PubMed  Google Scholar 

  14. Singh M, Salnikova M, editors. Novel approaches and strategies for biologics, vaccines and cancer therapies. Academic Press, Elsevier; 2015.

  15. Levene AP, Singh G, Palmieri C. Therapeutic monoclonal antibodies in oncology. J R Soc Med. 2005;98:146–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Simpson A, Caballero O. Monoclonal antibodies for the therapy of cancer. BMC Proc. 2014;8:6–8.

    Article  Google Scholar 

  17. Harris TJ, Drake CG. Primer on tumor immunology and cancer immunotherapy. J Immunother Cancer. 2013;1:1–9.

    Article  Google Scholar 

  18. Kimiz-Gebologlu I, Gulce-Iz S, Biray-Avci C. Monoclonal antibodies in cancer immunotherapy. Mol Biol Rep. 2018;45:2935–40.

    Article  CAS  PubMed  Google Scholar 

  19. Lefebvre ML, Krause SW, Salcedo M, Nardin A. Ex vivo-activated human macrophages kill chronic lymphocytic leukemia cells in the presence of rituximab: mechanism of antibody-dependent cellular cytotoxicity and impact of human serum. J Immunother. 2006;29:388–97.

    Article  CAS  PubMed  Google Scholar 

  20. van de Donk NWCJ. Immunomodulatory effects of CD38-targeting antibodies. Immunol Lett. 2018;199:16–22.

    Article  PubMed  CAS  Google Scholar 

  21. Segal DM, Weiner GJ, Weiner LM. Bispecific antibodies in cancer therapy. Curr Opin Immunol. 1999;11:558–62.

    Article  CAS  PubMed  Google Scholar 

  22. Fan G, Wang Z, Hao M, Li J. Bispecific antibodies and their applications. J Hematol Oncol. 2015;8:130.

  23. Spiess C, Zhai Q, Carter PJ. Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol Immunol. 2015;67:95–106.

    Article  CAS  PubMed  Google Scholar 

  24. Chelius DC, Gruber P, Plöscher M, Liedtke R, Gansberger E, Hess J, et al. Structural and functional characterization of the trifunctional antibody catumaxomab. MAbs 2010;2:309–19.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kubota T, Niwa R, Satoh M, Akinaga S, Shitara K, Hanai N. Engineered therapeutic antibodies with improved effector functions. Cancer Sci. 2009;100:1566–72.

    Article  CAS  PubMed  Google Scholar 

  26. Papachristos A, Pippa N, Demetzos C, Sivolapenko G. Antibody-drug conjugates: a mini-review. The synopsis of two approved medicines. Drug Deliv. 2016;23:1662–6.

    CAS  PubMed  Google Scholar 

  27. Thomas A, Teicher BA, Hassan R. Antibody–drug conjugates for cancer therapy. Lancet Oncol. 2016;17:e254–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Abdollahpour-Alitappeh M, Lotfinia M, Gharibi T, Mardaneh J, Farhadihosseinabadi B, Larki P, et al. Antibody–drug conjugates (ADCs) for cancer therapy: Strategies, challenges, and successes. J Cell Physiol. 2019;234:5628–42.

    Article  CAS  PubMed  Google Scholar 

  29. Nejadmoghaddam M, Minai-tehrani A, Ghahremanzadeh R. Antibody-drug conjugates: possibilities and challenges. Avicenna J Med Biotechnol. 2019;11:3–23.

  30. Chen H, Lin Z, Arnst KE, Miller DD, Li W. Tubulin inhibitor-based antibody-drug conjugates for cancer therapy. Molecules. 2017;22:1281.

  31. Gheibi Hayat SM, Sahebkar AH. Antibody drug conjugates for cancer therapy. J Babol Univ Med Sci. 2017;19:20–7.

    Google Scholar 

  32. Fu Y, Ho M. DNA damaging agent-based antibody-drug conjugates for cancer therapy. Antib Ther. 2018;1:43–53.

    CAS  Google Scholar 

  33. Sau S, Alsaab HO, Kashaw SK, Tatiparti K, Iyer AK. Advances in antibody–drug conjugates: A new era of targeted cancer therapy. Drug Discov Today. 2017;22:1547–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dyck L, Mills KHG. Immune checkpoints and their inhibition in cancer and infectious diseases. Eur J Immunol. 2017;47:765–79.

    Article  CAS  PubMed  Google Scholar 

  35. Huang PW, Chang JWC. Immune checkpoint inhibitors win the 2018 Nobel Prize. Biomed J 2019;42:299–306.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Nat Publ Gr. 2018;118:9–16.

    CAS  Google Scholar 

  37. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271:1734–6.

    Article  CAS  PubMed  Google Scholar 

  38. Chambers CA, Kuhns MS, Egen JG, Allison JP. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor Immunotherapy. Annu Rev Immunol. 2001;19:565–94.

    Article  CAS  PubMed  Google Scholar 

  39. Chang J-F, Phillips J, Kufe D, Greenburg G. MUC1 can function as a potent negative regulator of T cell activation. FASEB J. 1998;12:405–13.

    Google Scholar 

  40. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Moya-Horno I, Viteri S, Karachaliou N, Rosell R. Combination of immunotherapy with targeted therapies in advanced non-small cell lung cancer (NSCLC). Ther Adv Med Oncol. 2018;10:1–12.

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007;19:813–24.

    Article  CAS  PubMed  Google Scholar 

  44. Fessler MB, Rudel, Lawrence L, Brown M. 基因的改变NIH public access. Bone 2008;23:1–7.

    Google Scholar 

  45. Guo L, Zhang H, Chen B. Nivolumab as programmed death-1 (PD-1) inhibitor for targeted immunotherapy in tumor. J Cancer. 2017;8:410–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cyprian FS, Akhtar S, Gatalica Z, Vranic S. Targeted immunotherapy with a checkpoint inhibitor in combination with chemotherapy: A new clinical paradigm in the treatment of triple-negative breast cancer. Bosn J Basic Med Sci. 2019;19:227–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gaillard SL, Secord AA, Monk B. The role of immune checkpoint inhibition in the treatment of ovarian cancer. Gynecol Oncol Res Pr. 2016;3:1–14.

    Google Scholar 

  49. Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways similarities, differences, and implications of their inhibition. Am J Clin Oncol. Cancer Clin Trials. 2016;39:98–106.

    CAS  Google Scholar 

  50. Hargadon KM, Johnson CE, Williams CJ. Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol. 2018;62:29–39. (July)

    Article  CAS  PubMed  Google Scholar 

  51. Ramagopal UA, Liu W, Garrett-Thomson SC, Bonanno JB, Yan Q, Srinivasan M, et al. Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab. Proc Natl Acad Sci USA. 2017;114:E4223–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. García-Fernandez C, Fornaguera C, Borrós S. Nanomedicine in non-small cell lung cancer: from conventional treatments to immunotherapy. Cancers 2020;12:1609.

    Article  PubMed Central  CAS  Google Scholar 

  53. Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Mark E. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer. 2008;8:299–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Subklewe M, Von Bergwelt-Baildon M, Humpe A. Chimeric antigen receptor T cells: a race to revolutionize cancer therapy. Transfus Med Hemotherapy. 2019;46:15–24.

    Article  Google Scholar 

  55. Rohaan MW, Wilgenhof S, Haanen JBAG. Adoptive cellular therapies: the current landscape. Virchows Arch. 2019;474:449–61.

    Article  PubMed  Google Scholar 

  56. Nethanel T, Moav N, Ran M, Witz IP. Separation of tumor-seeking small lymphocytes and tumor cells using Percoll velocity gradients. J Immunol Methods. 1981;41:43–56.

    Article  CAS  PubMed  Google Scholar 

  57. Geukes Foppen MH, Donia M, Svane IM, Haanen JBAG. Tumor-infiltrating lymphocytes for the treatment of metastatic cancer. Mol Oncol. 2015;9:1918–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Dudley ME, Wunderlich JR, Shelton TE, Even J, Rosenberg SA. Generation of tumor-infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients. J Immunother. 2003;26:332–42.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005;202:907–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Idos GE, Kwok J, Bonthala N, Kysh L, Gruber SB, Qu C. The prognostic implications of tumor infiltrating lymphocytes in colorectal cancer: a systematic review and meta-analysis. Sci Rep. 2020;10:1–14.

    Article  CAS  Google Scholar 

  61. Monaco SE, Pantanowitz L, Xing J, Cuda J, Kammula US. Cytologic evaluation of tumor-infiltrating lymphocytes for adoptive cell therapy. Am J Clin Pathol. 2020;153:513–23.

    Article  CAS  PubMed  Google Scholar 

  62. Smith-garvin JE, Koretzky GA, Jordan MS. NIH public access - T cell activation. Immunology 2010;27:591–619.

    Article  CAS  Google Scholar 

  63. Abraham RT, Weiss A. Jurkat T cells and development of the T-cell receptor signalling paradigm. Nat Rev Immunol. 2004;4:301–8.

    Article  CAS  PubMed  Google Scholar 

  64. Linnemann C, Schumacher TNM, Bendle GM. T-cell receptor gene therapy: Critical parameters for clinical success. J Invest Dermatol. 2011;131:1806–16.

    Article  CAS  PubMed  Google Scholar 

  65. Nawaz W, Xu S, Li Y, Huang B, Wu X, Wu Z. Nanotechnology and immunoengineering: How nanotechnology can boost CAR-T therapy. Acta Biomater. 2020;109:21–36.

    Article  CAS  PubMed  Google Scholar 

  66. Almåsbak H, Aarvak T, Vemuri MC. CAR T cell therapy: a game changer in cancer treatment. J Immunol Res. 2016;2016:10.

  67. Mohanty R, Chowdhury CR, Arega S, Sen P, Ganguly P, Ganguly N. CAR T cell therapy: A new era for cancer treatment (review). Oncol Rep. 2019;42:2183–95.

    CAS  PubMed  Google Scholar 

  68. Chimeric T, Receptor A, Grywalska E, Sosnowska-pasiarska B, Smok-kalwat J. Paving the way toward successful multiple myeloma. Cells. 2020;9:983.

  69. D’Aloia MM, Zizzari IG, Sacchetti B, Pierelli L, Alimandi M. CAR-T cells: the long and winding road to solid tumors review-article. Cell Death Dis. 2018;9:282.

  70. Nam J, Son S, Park KS, Zou W, Shea LD, Moon JJ. Cancer nanomedicine for combination cancer immunotherapy. Nat Rev Mater. 2019;4:398–414.

    Article  Google Scholar 

  71. Garner H, de Visser KE. Immune crosstalk in cancer progression and metastatic spread: a complex conversation. Nat Rev Immunol. 2020;20:483–97.

    Article  CAS  PubMed  Google Scholar 

  72. Muenst S, Läubli H, Soysal SD, Zippelius A, Tzankov A, Hoeller S. The immune system and cancer evasion strategies: Therapeutic concepts. J Intern Med. 2016;279:541–62.

    Article  CAS  PubMed  Google Scholar 

  73. Minutolo NG, Hollander EE, Powell DJJ. The emergence of universal immune receptor t cell therapy for cancer. Front Oncol. 2019;9:176.

  74. Oki Y, Younes A. Heat shock protein-based cancer vaccines. Expert Rev Vaccines. 2004;3:403–11.

    Article  CAS  PubMed  Google Scholar 

  75. Wada S, Yada E, Ohtake J, Sasada T. Personalized peptide vaccines for cancer therapy: Current progress and state of the art. Expert Rev Precis Med Drug Dev. 2017;2:371–81.

    Article  Google Scholar 

  76. Ward S, Casey D, Labarthe MC, Whelan M, Dalgleish A, Pandha H, et al. Immunotherapeutic potential of whole tumour cells. Cancer Immunol Immunother. 2002;51:351–7.

    Article  PubMed  Google Scholar 

  77. Hirschowitz EA, Mullins A, Prajapati D, Baeker T, Kloecker G, Foody T, et al. Pilot study of 1650-G: A simplified cellular vaccine for lung cancer. J Thorac Oncol. 2011;6:169–73.

    Article  PubMed  Google Scholar 

  78. Saxena M, Balan S, Roudko V, Bhardwaj N. Towards superior dendritic-cell vaccines for cancer therapy. Nat Biomed Eng. 2018;2:341–4.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Higano CS, Small EJ, Schellhammer P, Yasothan U, Gubernick S, Kirkpatrick P, et al. Sipuleucel-T. Nat Rev Drug Discov. 2010;9:513–4.

    Article  CAS  PubMed  Google Scholar 

  80. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines-a new era in vaccinology. Nat Rev Drug Discov. 2018;17:261–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Jahanafrooz Z, Baradaran B, Mosafer J, Hashemzaei M, Rezaei T, Mokhtarzadeh A, et al. Comparison of DNA and mRNA vaccines against cancer. Drug Discov Today. 2020;25:552–60.

    Article  PubMed  Google Scholar 

  82. Zhao Y, Huang L. Lipid nanoparticles for gene delivery. Adv Genet. 2014;88:13–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Islam MA, Reesor EKG, Xu Y, Zope HR, Zetter BR, Shi J. Biomaterials for mRNA delivery. Biomater Sci. 2015;3:1519–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hong HS, Koch SD, Scheel B, Gnad-Vogt U, Schröder A, Kallen KJ, et al. Distinct transcriptional changes in non-small cell lung cancer patients associated with multi-antigenic RNActive® CV9201 immunotherapy. Oncoimmunology. 2016;5:e1249560.

  85. Wilhelm S, Tavares AJ, Dai Q, Ohta S, Audet J, Dvorak HF, et al. Analysis of nanoparticle delivery to tumours. Nat Rev Mater. 2016;1:16014.

  86. Jiang W, Von Roemeling CA, Chen Y, Qie Y, Liu X, Chen J, et al. Designing nanomedicine for immuno-oncology. Nat Biomed Eng. 2017;1:1–11.

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  89. Shi J, Kantoff PW, Wooster R, Farokhzad OC. Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer. 2017;17:20–37.

    Article  CAS  PubMed  Google Scholar 

  90. Nakamura T, Harashima H. Integration of nano drug-delivery system with cancer immunotherapy. Ther Deliv. 2017;8:987–1000.

    Article  CAS  PubMed  Google Scholar 

  91. Jovčevska I, Muyldermans S. The therapeutic potential of nanobodies. BioDrugs 2020;34:11–26.

    Article  PubMed  CAS  Google Scholar 

  92. Yang EY, Shah K. Nanobodies: next generation of cancer diagnostics and therapeutics. Front Oncol. 2020;10:1182.

  93. Al-Baradie RS. Nanobodies as versatile tools: a focus on targeted tumor therapy, tumor imaging and diagnostics. Hum Antibodies. 2020;1:1–14.

    Google Scholar 

  94. Barenholz Y. Doxil® - the first FDA-approved nano-drug: lessons learned. J Control Release. 2012;160:117–34.

    Article  CAS  PubMed  Google Scholar 

  95. Kuai R, Ochyl LJ, Bahjat KS, Schwendeman A, Moon JJ. Designer vaccine nanodiscs for personalized cancer immunotherapy. Nat Mater. 2017;16:489–98.

    Article  CAS  PubMed  Google Scholar 

  96. Kuai R, Yuan W, Son S, Nam J, Xu Y, Fan Y, et al. Elimination of established tumors with nanodisc-based combination chemoimmunotherapy. Sci Adv. 2018;4:1–14.

    Article  CAS  Google Scholar 

  97. van der Meel R, Sulheim E, Shi Y, Kiessling F, Mulder WJM, Lammers T. Smart cancer nanomedicine. Nat Nanotechnol. 2019;14:1007–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Zhang F, Stephan SB, Ene CI, Smith TT, Holland EC, Stephan MT. Nanoparticles that reshape the tumor milieu create a therapeutic window for effective T-cell therapy in solid malignancies. Cancer Res. 2018;78:3718–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Liu Z, Jiang W, Nam J, Moon JJ, Kim BYS. Immunomodulating nanomedicine for cancer therapy. Nano Lett. 2018;18:6655–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Goldberg MS. Improving cancer immunotherapy through nanotechnology. Nat Rev Cancer. 2019;19:587–602.

    Article  CAS  PubMed  Google Scholar 

  102. Fan YN, Li M, Luo YL, Chen Q, Wang L, Zhang HB, et al. Cationic lipid-assisted nanoparticles for delivery of mRNA cancer vaccine. Biomater Sci. 2018;6:3009–18.

    Article  CAS  PubMed  Google Scholar 

  103. Fornaguera C, Guerra-rebollo M, Lázaro MÁ, Castells-sala C, Meca-cortés O, Ramos-pérez V, et al. mRNA delivery system for targeting antigen-presenting cells in vivo. 2018;7:1–11.

  104. Yuan H, Jiang W, Von Roemeling CA, Qie Y, Liu X, Chen Y, et al. Multivalent bi-specific nanobioconjugate engager for targeted cancer immunotherapy. Nat Nanotechnol. 2017;12:763–9.

    Article  CAS  PubMed  Google Scholar 

  105. Bhutani D, Vaishampayan UN. Monoclonal antibodies in oncology therapeutics: Present and future indications. Expert Opin Biol Ther. 2013;13:269–82.

    Article  CAS  PubMed  Google Scholar 

  106. Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 2006;366:2–16.

    Article  CAS  PubMed  Google Scholar 

  107. Agustoni F, Suda K, Yu H, Ren S, Rivard CJ, Ellison K, et al. EGFR-directed monoclonal antibodies in combination with chemotherapy for treatment of non-small-cell lung cancer: an updated review of clinical trials and new perspectives in biomarkers analysis. Cancer Treat Rev. 2019;72:15–27.

    Article  CAS  PubMed  Google Scholar 

  108. Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009;373:1525–31.

    Article  CAS  PubMed  Google Scholar 

  109. Bertino EM, McMichael EL, Mo X, Trikha P, Davis M, Paul B, et al. A phase I trial to evaluate antibody-dependent cellular cytotoxicity of cetuximab and lenalidomide in advanced colorectal and head and neck cancer. Mol Cancer Ther. 2016;15:2244–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Zhou X, Hu W, Qin X. The role of complement in the mechanism of action of rituximab for B‐cell lymphoma: implications for therapy. Oncologist 2008;13:954–66.

    Article  CAS  PubMed  Google Scholar 

  111. Schütze K, Petry K, Hambach J, Schuster N, Albrecht B, Haag F, et al. CD38-specific biparatopic heavy chain antibodies display potent complement-dependent cytotoxicity against multiple myeloma. Cells 2018;9:1–11.

    Google Scholar 

  112. Pereira NA, Chan KF, Lin PC, Song Z. The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity. MAbs 2018;10:693–711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Linke R, Klein A, Seimetz D. Catumaxomab: clinical development and future directions. MAbs 2010;2:129–36.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Seimetz D. Novel monoclonal antibodies for cancer treatment: the trifunctional an-tibody catumaxomab (Removab®). J Cancer. 2011;2:309–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Schmitt M, Schmitt A, Reinhardt P, Thess B, Manfras B, Lindhofer H, et al. Opsonization with a trifunctional bispecific (alphaCD3 x alphaEpCAM) antibody results in efficient lysis in vitro and in vivo of EpCAM positive tumor cells by cytotoxic T lymphocytes. Int J Oncol. 2004;25:841–8.

    CAS  PubMed  Google Scholar 

  116. Buchner A, Riesenberg R, Feicht W, Lindhofer H. Lysis of prostate carcinoma cells by bispecifie antibodies (αEpCAM x αCD3) -visualization by a video incubation system. Eur J Cancer. 2001;37:911–7. SUPPL. 1

    Article  Google Scholar 

  117. Zeidler R, Mysliwietz J, Csánady M, Walz A, Ziegler I, Schmitt B, et al. The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumour cells. Br J Cancer. 2000;83:261–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Dahlén E, Veitonmäki N, Norlén P. Bispecific antibodies in cancer immunotherapy. Ther Adv Vaccines Immunother 2018;6:3–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Brischwein K, Parr L, Pflanz S, Volkland J, Lumsden J, Klinger M, et al. Strictly target cell-dependent activation of T cells by bispecific single-chain antibody constructs of the BiTE class. J Immunother. 2007;30:798–807.

    Article  CAS  PubMed  Google Scholar 

  120. Ph D, Schuh AC, Ribera J, Ph D, Wei A. Blinatumomab versus chemotherapy for advanced acute lymphoblastic. Leukemia 2018;376:836–47.

    Google Scholar 

  121. Gaiser OJ, Piotukh K, Ponnuswamy MN, Planas A, Borriss R, Heinemann U. Structural basis for the substrate specificity of a Bacillus 1,3-1,4-β-glucanase. J Mol Biol. 2006;357:1211–25.

    Article  CAS  PubMed  Google Scholar 

  122. Finkelmeier F, Waidmann O, Trojan J. Nivolumab for the treatment of hepatocellular carcinoma. Expert Rev Anticancer Ther. 2018;18:1169–75.

    Article  CAS  PubMed  Google Scholar 

  123. Xu JX, Maher VE, Zhang L, Tang S, Sridhara R, Ibrahim A, et al. FDA approval summary: nivolumab in advanced renal cell carcinoma after anti‐angiogenic therapy and exploratory predictive biomarker analysis. Oncologist 2017;22:311–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Kazandjian D, Suzman DL, Blumenthal G, Mushti S, He K, Libeg M, et al. FDA approval summary: nivolumab for the treatment of metastatic non‐small cell lung cancer with progression on or after platinum‐based chemotherapy. Oncologist 2016;21:634–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Kasamon YL, de Claro RA, Wang Y, Shen YL, Farrell AT, Pazdur R. FDA approval summary: nivolumab for the treatment of relapsed or progressive classical Hodgkin lymphoma. Oncologist 2017;22:585–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Murakami S. Durvalumab for the treatment of non-small cell lung cancer. Expert Rev Anticancer Ther. 2019;19:1009–16.

    Article  CAS  PubMed  Google Scholar 

  127. Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, et al. Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer. N. Engl J Med. 2018;379:2040–51.

    Article  CAS  PubMed  Google Scholar 

  128. Bradford D, Demko S, Jin S, Mishra‐Kalyani P, Beckles AR, Goldberg KB, et al. FDA accelerated approval of pembrolizumab for recurrent locally advanced or metastatic merkel cell carcinoma. Oncologist. 2020;25:e1077–82.

  129. Suzman DL, Agrawal S, Ning Y, Maher VE, Fernandes LL, Karuri S, et al. FDA approval summary: atezolizumab or pembrolizumab for the treatment of patients with advanced urothelial carcinoma ineligible for cisplatin‐containing chemotherapy. Oncologist 2019;24:563–9.

    Article  CAS  PubMed  Google Scholar 

  130. Fashoyin‐Aje L, Donoghue M, Chen H, He K, Veeraraghavan J, Goldberg KB, et al. FDA approval summary: pembrolizumab for recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma expressing PD‐L1. Oncologist 2019;24:103–9.

    Article  PubMed  CAS  Google Scholar 

  131. Pai‐Scherf L, Blumenthal GM, Li H, Subramaniam S, Mishra‐Kalyani PS, He K, et al. FDA approval summary: pembrolizumab for treatment of metastatic non‐small cell lung cancer: first‐line therapy and beyond. Oncologist 2017;22:1392–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Larkins E, Blumenthal GM, Yuan W, He K, Sridhara R, Subramaniam S, et al. FDA approval summary: pembrolizumab for the treatment of recurrent or metastatic head and neck squamous cell carcinoma with disease progression on or after platinum‐containing chemotherapy. Oncologist 2017;22:873–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Maly J, Alinari L. Pembrolizumab in classical Hodgkin’s lymphoma. Eur J Haematol. 2016;97:219–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Chuk MK, Chang JT, Theoret MR, Sampene E, He K, Weis SL, et al. FDA Approval summary: accelerated approval of pembrolizumab for second-line treatment of metastatic melanoma. Clin Cancer Res. 2017;23:5666–70.

    Article  CAS  PubMed  Google Scholar 

  135. Choi B, McBride A, Scott AJ. Treatment with pembrolizumab after hypersensitivity reaction to nivolumab in a patient with hepatocellular carcinoma. Am J Heal Pharm. 2019;76:1749–52.

    Article  Google Scholar 

  136. Markham A, Duggan S. Cemiplimab: first global approval. 2018;78:1841–6.

  137. Reddy SM, Carroll E, Nanda R. Atezolizumab for the treatment of breast cancer. Expert Rev Anticancer Ther. 2020;20:151–8.

    Article  CAS  PubMed  Google Scholar 

  138. Weinstock C, Khozin S, Suzman D, Zhang L, Tang S, Wahby S, et al. U.S. Food and Drug Administration approval summary: Atezolizumab for metastatic non–small cell lung cancer. Clin Cancer Res. 2017;23:4534–9.

    Article  CAS  PubMed  Google Scholar 

  139. Gaiser MR, Bongiorno M, Brownell I. PD-L1 inhibition with avelumab for metastatic Merkel cell carcinoma. Expert Rev Clin Pharm. 2018;11:345–59.

    Article  CAS  Google Scholar 

  140. Rao A, Patel MR. A review of avelumab in locally advanced and metastatic bladder cancer. Ther Adv Urol. 2019;11:175628721882348.

    Article  Google Scholar 

  141. Lavaud P, Hamilou Z, Loriot Y, Massard C. Durvalumab in urothelial cancers. Expert Rev Anticancer Ther. 2018;18:311–8.

    Article  CAS  PubMed  Google Scholar 

  142. Philippidis A. Kymriah. First CAR-T cancer immunotherapy approved by FDA. 2017;4:8.

  143. Bouchkouj N, Kasamon YL, Claro RA De, George B, Lin X, Lee S, et al. FDA Approval summary: axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma. 2019;25:1702–9.

  144. Rodell CB, Arlauckas SP, Cuccarese MF, Garris CS, Li R, Ahmed MS, et al. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy. 2018;2:578–88.

  145. Cho N, Cheong T, Min JH, Wu JH, Lee SJ, Kim D, et al. A multifunctional core-shell nanoparticle for dendritic cell-based cancer immunotherapy. 2011;6:675–82.

  146. Schloßbauer A, Sauer AM, Cauda V, Schmidt A, Engelke H, Rothbauer U, et al. Cascaded photoinduced drug delivery to cells from multifunctional core-shell mesoporous silica. Adv Health Mater. 2012;1:316–20.

    Article  CAS  Google Scholar 

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

  148. Mi Y, Smith CC, Yang F, Qi Y, Roche KC, Serody JS, et al. A Dual immunotherapy nanoparticle improves T-cell activation and cancer immunotherapy. 2018;1706098:1–9.

  149. Luo M, Wang H, Wang Z, Cai H, Lu Z, Li Y, et al. A STING-activating nanovaccine for cancer immunotherapy. Nat Nanotechnol. 2017;12:648–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The Support of Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) from Generalitat de Catalunya for their support through SGR 2017 1559 grant is acknowledged. Financial support from Spanish Ministerio de Ciencia, Innovación y Universidades for the grant RTI2018-094734-B-C22. C.G-F would like to thank IQS for her Ph.D. fellowship. S.B. acknowledges Fundació Cellex research grant. Figures were created using biorender.com.

Author information

Authors and Affiliations

  1. Grup d’Enginyeria de Materials (Gemat), Institut Químic de Sarrià (IQS), Univeritat Ramon Llull (URL), Barcelona, Spain

    Coral García-Fernández, Anna Saz, Cristina Fornaguera & Salvador Borrós

Authors
  1. Coral García-Fernández
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anna Saz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cristina Fornaguera
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Salvador Borrós
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cristina Fornaguera.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Disclaimer

The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

García-Fernández, C., Saz, A., Fornaguera, C. et al. Cancer immunotherapies revisited: state of the art of conventional treatments and next-generation nanomedicines. Cancer Gene Ther 28, 935–946 (2021). https://doi.org/10.1038/s41417-021-00333-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-021-00333-5

This article is cited by

Search

Advanced search

Quick links