Skip to main content
SpringerLink
Log in

Multiple myeloma gammopathies

BCMA peptide-engineered nanoparticles enhance induction and function of antigen-specific CD8+ cytotoxic T lymphocytes against multiple myeloma: clinical applications

  • Article
  • Published:
Leukemia Submit manuscript

A Correction to this article was published on 16 January 2020

This article has been updated

Abstract

The purpose of these studies was to develop and characterize B-cell maturation antigen (BCMA)-specific peptide-encapsulated nanoparticle formulations to efficiently evoke BCMA-specific CD8+ cytotoxic T lymphocytes (CTL) with poly-functional immune activities against multiple myeloma (MM). Heteroclitic BCMA72−80 [YLMFLLRKI] peptide-encapsulated liposome or poly(lactic-co-glycolic acid) (PLGA) nanoparticles displayed uniform size distribution and increased peptide delivery to human dendritic cells, which enhanced induction of BCMA-specific CTL. Distinct from liposome-based nanoparticles, PLGA-based nanoparticles demonstrated a gradual increase in peptide uptake by antigen-presenting cells, and induced BCMA-specific CTL with higher anti-tumor activities (CD107a degranulation, CTL proliferation, and IFN-γ/IL-2/TNF-α production) against primary CD138+ tumor cells and MM cell lines. The improved functional activities were associated with increased Tetramer+/CD45RO+ memory CTL, CD28 upregulation on Tetramer+ CTL, and longer maintenance of central memory (CCR7+ CD45RO+) CTL, with the highest anti-MM activity and less differentiation into effector memory (CCR7− CD45RO+) CTL. These results provide the framework for therapeutic application of PLGA-based BCMA immunogenic peptide delivery system, rather than free peptide, to enhance the induction of BCMA-specific CTL with poly-functional Th1-specific anti-MM activities. These results demonstrate the potential clinical utility of PLGA nanotechnology-based cancer vaccine to enhance BCMA-targeted immunotherapy against myeloma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Change history

References

  1. Miliotou AN, Papadopoulou LC.CAR T-cell therapy: a new era in cancer immunotherapy.Curr Pharm Biotechnol. 2018;19:5–18.

    PubMed  Google Scholar 

  2. Legut M, Sewell AK. Designer T-cells and T-cell receptors for customized cancer immunotherapies. Curr Opin Pharm. 2018;41:96–103.

    CAS  Google Scholar 

  3. Ping Y, Liu C, Zhang Y. T-cell receptor-engineered T cells for cancer treatment: current status and future directions. Protein Cell. 2018;9:254–66.

    PubMed  Google Scholar 

  4. Salter AI, Pont MJ, Riddell SR. Chimeric antigen receptor-modified T cells: CD19 and the road beyond. Blood. 2018;131:2621–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Curran MA, Glisson BS. New hope for therapeutic cancer vaccines in the era of immune checkpoint modulation. Annu Rev Med. 2018. https://doi.org/10.1146/annurev-med-050217-121900.

  6. Chamani R, Ranji P, Hadji M, Nahvijou A, Esmati E, Alizadeh AM. Application of E75 peptide vaccine in breast cancer patients: a systematic review and meta-analysis. Eur J Pharm. 2018;831:87–93.

    CAS  Google Scholar 

  7. Bae J, Carrasco R, Lee AH, Prabhala R, Tai YT, Anderson KC, et al. Identification of novel myeloma-specific XBP1 peptides able to generate cytotoxic T lymphocytes: a potential therapeutic application in multiple myeloma. Leukemia. 2011;25:1610–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Bae J, Tai YT, Anderson KC, Munshi NC. Novel epitope evoking CD138 antigen-specific cytotoxic T lymphocytes targeting multiple myeloma and other plasma cell disorders. Br J Haematol. 2011;155:349–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Bae J, Song W, Smith R, Daley J, Tai YT, Anderson KC, et al. A novel immunogenic CS1-specific peptide inducing antigen-specific cytotoxic T lymphocytes targeting multiple myeloma. Br J Haematol. 2012;157:687–701.

    CAS  PubMed  Google Scholar 

  10. Nooka AJ, Wang M, Yee AJ, Kaufman J, Bae J, Peterkin D, et al. Safety and Immunogenicity of PVX-410 Vaccine ± lenalidomide in smoldering multiple myeloma. JAMA Oncol. 2018;4:e183267. https://doi.org/10.1001/jamaoncol.2018.3267.

  11. Tran T, Blanc C, Granier C, Saldmann A, Tanchot C, Tartour E. Therapeutic cancer vaccine: building the future from lessons of the past. Semin Immunopathol. 2018. https://doi.org/10.1007/s00281-018-0691-z.

  12. Scharping NE, Delgoffe GM. Tumor microenvironment metabolism: a new checkpoint for anti-tumor immunity. Vaccinnes (Basel). 2016;4:E46.

    Google Scholar 

  13. Strauss J, Madan RA, Gulley JL. Considerations for the combination of anticancer vaccines and immune checkpoint inhibitors. Expert Opin Biol Ther. 2016;16:895–901.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Moreaux J, Legouffe E, Jourdan E, Quittet P, Re’me T, Lugagne C, et al. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood. 2004;103:3148–57.

    CAS  PubMed  Google Scholar 

  15. O’Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med. 2004;199:91–8.

    PubMed  PubMed Central  Google Scholar 

  16. Coquery CM, Erickson LD. Regulatory roles of the tumor necrosis factor receptor BCMA. Crit Rev Immunol. 2012;32:287–305.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Bae J, Samur M, Richardson P, Munshi NC, Anderson KC. Selective targeting of multiple myeloma by B cell maturation antigen (BCMA)-specific central memory CD8+ cytotoxic T lymphocytes: immunotherapeutic application in vaccination and adoptive immunotherapy. Leukemia. 2019. https://doi.org/10.1038/s41375-019-0414-z. [Epub ahead of print].

  18. Sahoo SK, Ma W, Labhasetwar V. Efficacy of transferrin-conjugated paclitaxel-loaded nanoparticles in a murine model of prostate cancer. Int J Cancer. 2004;112:335–40.

    CAS  PubMed  Google Scholar 

  19. Brudno JN, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for lymphoma. Nat Rev Clin Oncol. 2018;15:31–46.

    CAS  PubMed  Google Scholar 

  20. O’Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JD, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med. 2017;9:eaaa0984.

    PubMed  PubMed Central  Google Scholar 

  21. Parvizpour Sepideh, Razmara Jafar, Omidi Yadollah. Breast cancer vaccination comes to age: impacts of bioinformatics. Bioimpacts. 2018;8:223–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Chiang CL, Kandalaft LE, Tanyi J, Hagemann AR, Motz GT, Svoronos N, et al. A dendritic cell vaccine pulsed with autologous hypochlorous acid-oxidized ovarian cancer lysate primes effective broad antitumor immunity: from bench to bedside. Clin Cancer Res. 2013;19:4801–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15:47–62.

    CAS  PubMed  Google Scholar 

  24. Kenderian SS, Porter DL, Gill S. Chimeric antigen receptor T cells and hematopoietic cell transplantation: how not to put the CART before the horse. Biol Blood Marrow Transpl. 2017;23:235–46.

    CAS  Google Scholar 

  25. Schwarzbich MA, Witzens-Harig M. Cellular immunotherapy in B-cell malignancy. Oncol Res Treat. 2017;40:674–81.

    CAS  PubMed  Google Scholar 

  26. Buddolla AL, Kim S. Recent insights into the development of nucleic acid-based nanoparticless for tumor-targeted drug delivery. Colloids Surf B Biointerfaces. 2018;172:315–22.

    CAS  PubMed  Google Scholar 

  27. Deshantri AK, Varela Moreira A, Ecker V, Mandhane SN, Schiffelers RM, Buchner M, et al. Nanomedicines for the treatment of hematological malignancies. J Control Release. 2018;287:194–215.

    CAS  PubMed  Google Scholar 

  28. Iqbal J, Abbasi BA, Ahmad R, Mahmood T, Ali B, Khalil AT, et al. Nanomedicines for developing cancer nanotherapeutics: from benchtop to bedside and beyond. Appl Microbiol Biotechnol. 2018;102:9449–70.

    CAS  PubMed  Google Scholar 

  29. Tabassum N, Verma V, Kumar M, Kumar A, Singh B. Nanomedicine in cancer stem cell therapy: from fringe to forefront. Cell Tissue Res. 2018. https://doi.org/10.1007/s00441-018-2928-5.

  30. Zhang Y, Zhang P, Zhu T. Ovarian carcinoma biological nanotherapy: comparison of the advantages and drawbacks of lipid, polymeric, and hybrid nanoparticles for cisplatin delivery. Biomed Pharm. 2018;109:475–83.

    Google Scholar 

  31. Desfrançois C, Auzély R, Texier I. Lipid nanoparticles and their hydrogel composites for drug delivery: a review. Pharmaceuticals (Basel). 2018;11:E118. https://doi.org/10.3390/ph11040118.

    Article  CAS  Google Scholar 

  32. Hong SJ, Ahn MH, Lee YW, Pal S, Sangshetti J, Arote RB. Biodegradable polymeric nanocarrier-based immunotherapy in hepatitis vaccination. Adv Exp Med Biol. 2018;1078:303–20.

    CAS  PubMed  Google Scholar 

  33. Aftab S, Shah A, Nadhman A, Kurbanoglu S, Aysıl Ozkan S, Dionysiou DD, et al. Nanomedicine: an effective tool in cancer therapy. Int J Pharm. 2018;540:132–49.

    CAS  PubMed  Google Scholar 

  34. Aw MS, Paniwnyk L. Overcoming T. gondii infection and intracellular protein nanocapsules as biomaterials for ultrasonically controlled drug release. Biomater Sci. 2017;5:1944–61.

    CAS  PubMed  Google Scholar 

  35. Bayford R, Rademacher T, Roitt I, Wang SX. Emerging applications of nanotechnology for diagnosis and therapy of disease: a review. Physiol Meas. 2017;38:R183–R203.

    PubMed  Google Scholar 

  36. Tang Q, Yu B, Gao L, Cong H, Song N, Lu C. Stimuli responsive nanoparticles for controlled anti-cancer drug release. Curr Med Chem. 2018;25:1837–66.

    CAS  PubMed  Google Scholar 

  37. Jahan ST, Sadat SM, Haddadi A. Design and immunological evaluation of anti-CD205-tailored PLGA-based nanoparticulate cancer vaccine. Int J Nanomed. 2018;13:367–86.

    CAS  Google Scholar 

  38. Kim H, Niu L, Larson P, Kucaba TA, Murphy KA, James BR, et al. Polymeric nanoparticles encapsulating novel TLR7/8 agonists as immunostimulatory adjuvants for enhanced cancer immunotherapy. Biomaterials. 2018;164:38–53.

    CAS  PubMed  Google Scholar 

  39. Wang D, Sun Y, Liu Y, Meng F, Lee RJ. Clinical translation of immunoliposomes for cancer therapy: recent perspectives. Expert Opin Drug Deliv. 2018;15:893–903.

    CAS  PubMed  Google Scholar 

  40. Graziani SR, Vital CG, Morikawa AT, Van Eyll BM, Fernandes Junior HJ, Kalil Filho R, et al. Phase II study of paclitaxel associated with lipid core nanoparticles (LDE) as third-line treatment of patients with epithelial ovarian carcinoma. Med Oncol. 2017;34:151.

    PubMed  Google Scholar 

  41. Grabbe S, Haas H, Diken M, Kranz LM, Langguth P, Sahin U. Translating nanoparticulate-personalized cancer vaccines into clinical applications: case study with RNA-lipoplexes for the treatment of melanoma. Nanomedicine (Lond). 2016;11:2723–34.

    CAS  Google Scholar 

  42. Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M, et al. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomized, double-blind, phase 3 trial. Lancet Oncol. 2014;15:59–68.

    CAS  PubMed  Google Scholar 

  43. Vansteenkiste JF, Vanakesa T, De Pas T, Zielinski M, Kim MS, Jassem J, et al. MAGRIT, a double-blind, randomized, placebo-controlled Phase III study to assess the efficacy of the RecMAGE-A3 + AS15 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-Positive non-small cell lung cancer (NSCLC). Ann Oncol. 2014;25:409–16.

    Google Scholar 

  44. Kruit WHJ, Suciu S, Dreno B, Mortier L, Robert C, Chiarion-Sileni V, et al. Selection of immunostimulant AS15 for active immunization with MAGE-A3 protein: results of a randomized phase II study of the European Organization for Research and Treatment of Cancer Melanoma Group in Metastatic Melanoma. J Clin Oncol. 2013;31:2413–20.

    CAS  PubMed  Google Scholar 

  45. Vansteenkiste JF, Cho BC, Vanakesa T, De Pas T, Zielinski M, Kim MS, et al. Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17:822–35.

    CAS  PubMed  Google Scholar 

  46. Limentani SA, Campone M, Dorval T, Curigliano G, de Boer R, Vogel C, et al. A non-randomized dose-escalation Phase I trial of a protein-based immunotherapeutic for the treatment of breast cancer patients with HER2-overexpressing tumors. Breast Cancer Res Treat. 2016;156:319–30.

    CAS  PubMed  Google Scholar 

  47. Berinstein NL, Karkada M, Oza AM, Odunsi K, Villella JA. Nemunai- tis JJ et al. Survivin-targeted immunotherapy drives robust polyfunctional T cell generation and differentiation in advanced ovarian cancer patients. Oncoimmunology. 2015;4:e1026529.

    PubMed  PubMed Central  Google Scholar 

  48. Saito T, Wada H, Yamasaki M, Miyata H, Nishikawa H, Sato E, et al. High expression of MAGE-A4 and MHC class I antigens in tumor cells and induction of MAGE-A4 immune responses are prognostic markers of CHP-MAGE-A4 cancer vaccine. Vaccine. 2014;32:5901–7.

    CAS  PubMed  Google Scholar 

  49. Bavananthasivam J, Alkie TN, Astill J, Abdul-Careem MF, Wootton SK, Behboudi S, et al. In ovo administration of Toll-like receptor ligands encapsulated in PLGA nanoparticles impede tumor development in chickens infected with Marek’s disease virus. Vaccine. 2018;36:4070–6.

    CAS  PubMed  Google Scholar 

  50. Thompson EA, Ols S, Miura K, Rausch K, Narum DL, Spångberg M, et al. TLR-adjuvanted nanoparticles vaccines differentially influence the quality and longevity of responses to malaria antigen Pfs25. JCI Insight. 2018;3:120692.

    PubMed  Google Scholar 

  51. Zupančič E, Curato C, Paisana M, Rodrigues C, Porat Z, Viana AS, et al. Rational design of nanoparticles towards targeting antigen-presenting cells and improved T cell priming. J Control Release. 2017;258:182–95.

    PubMed  Google Scholar 

  52. Salvador A, Igartua M, Hernandez RM, Pedraz JL. Combination of immune stimulating adjuvants with poly(lactide-co-glycolide) microspheres enhances the immune response of vaccines. Vaccine. 2012;30:589–96.

    CAS  PubMed  Google Scholar 

  53. Lee YR, Lee YH, Im SA, Kim K, Lee CK. Formulation and characterization of antigen-loaded PLGA nanoparticles for efficient cross-priming of the antigen. Immune Netw. 2011;11:163–8.

    PubMed  PubMed Central  Google Scholar 

  54. Kasturi SP, Skountzou I, Albrecht RA, Koutsonanos D, Hua T, Nakaya HI, et al. Programming the magnitude and persistence of antibody responses with innate immunity. Nature. 2011;470:543–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Allahyari M, Mohit E. Peptide/protein vaccine delivery system based on PLGA particles. Hum Vaccin Immunother. 2016;12:806–28.

    PubMed  Google Scholar 

  56. Silva AL, Rosalia RA, Varypataki E, Sibuea S, Ossendorp F, Jiskoot W. Poly-(lactic-co-glycolic-acid)-based particulate vaccines: particle uptake by dendritic cells is a key parameter for immune activation. Vaccine. 2015;33:847–54.

    CAS  PubMed  Google Scholar 

  57. Saini V, Jain V, Sudheesh MS, Jaganathan KS, Murthy PK, Kohli DV. Comparison of humoral and cell-mediated immune responses to cationic PLGA microspheres containing recombinant hepatitis B antigen. Int J Pharm. 2011;408:50–7.

    CAS  PubMed  Google Scholar 

  58. Feng L, Qi XR, Zhou XJ, Maitani Y, Wang SC, Jiang Y, et al. Pharmaceutical and immunological evaluation of a single-dose hepatitis B vaccine using PLGA microspheres. J Control Release. 2006;112:35–42.

    CAS  PubMed  Google Scholar 

  59. Jaganathan KS, Singh P, Prabakaran D, Mishra V, Vyas SP. Development of a single-dose stabilized poly(D,L-lactic-co-glycolic acid) microspheres-based vaccine against hepatitis B. J Pharm Pharm. 2004;56:1243–50.

    CAS  Google Scholar 

  60. Rosas JE, Pedraz JL, Hernandez RM, Gascon AR, Igartua M, Guz- man F, et al. Remarkably high antibody levels and protection against P. falciparum malaria in Aotus monkeys after a single immunisation of SPf66 encapsulated in PLGA microspheres. Vaccine. 2002;20:1707–10.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the Miriam and Sheldon G. Adelson Medical Research Foundation. This work was supported in part by grants from the National Institutes of Health Grants Special Program in Oncology Research Excellence (SPORE) P50 100707, RO1 CA 207237, and RO1 CA 050947. Dr. Kenneth C. Anderson is an American Cancer Society Clinical Research Professor.

Author information

Authors and Affiliations

  1. Dana-Farber Cancer Institute, Boston, MA, USA

    Jooeun Bae, Nikhil Munshi & Kenneth C. Anderson

  2. Harvard Medical School, Boston, MA, USA

    Jooeun Bae, Nikhil Munshi & Kenneth C. Anderson

  3. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Neha Parayath

  4. University of California San Diego, San Diego, CA, USA

    Wenxue Ma

  5. Northeastern University, Boston, MA, USA

    Mansoor Amiji

Authors
  1. Jooeun Bae
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Neha Parayath
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wenxue Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mansoor Amiji
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nikhil Munshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kenneth C. Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jooeun Bae.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bae, J., Parayath, N., Ma, W. et al. BCMA peptide-engineered nanoparticles enhance induction and function of antigen-specific CD8+ cytotoxic T lymphocytes against multiple myeloma: clinical applications. Leukemia 34, 210–223 (2020). https://doi.org/10.1038/s41375-019-0540-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-019-0540-7

  • Springer Nature Limited

This article is cited by

Search

Navigation