Advertisement

Cancer Immunology, Immunotherapy

, Volume 62, Issue 6, pp 983–987 | Cite as

BLyS levels correlate with vaccine-induced antibody titers in patients with glioblastoma lymphodepleted by therapeutic temozolomide

  • Luis Sanchez-Perez
  • Bryan D. Choi
  • Elizabeth A. Reap
  • Elias J. Sayour
  • Pamela Norberg
  • Robert J. Schmittling
  • Gerald E. Archer
  • James E. Herndon2nd
  • Duane A. Mitchell
  • Amy B. Heimberger
  • Darell D. Bigner
  • John H. SampsonEmail author
Original Article

Abstract

B lymphocyte stimulator (BLyS) is a cytokine involved in differentiation and survival of follicular B cells along with humoral response potentiation. Lymphopenia is known to precipitate dramatic elevation in serum BLyS; however, the use of this effect to enhance humoral responses following vaccination has not been evaluated. We evaluated BLyS serum levels and antigen-specific antibody titers in 8 patients undergoing therapeutic temozolomide (TMZ)-induced lymphopenia, with concomitant vaccine against a tumor-specific mutation in the epidermal growth factor receptor (EGFRvIII). Our studies demonstrate that TMZ-induced lymphopenia corresponded with spikes in serum BLyS that directly preceded the induction of anti-EGFRvIII antigen-specific antibody titers, in some cases as high as 1:2,000,000. Our data are the first clinical observation of BLyS serum elevation and greatly enhanced humoral immune responses as a consequence of chemotherapy-induced lymphopenia. These observations should be considered for the development of future vaccination strategies in the setting of malignancy.

Keywords

Temozolomide BLyS BAFF Lymphopenia Immunotherapy Vaccines 

Notes

Acknowledgments

The authors would like to thank Tecca Wright and Tracy A. Chewning for their assistance in the preparation of grant applications supporting these studies. In addition, special thanks go to Shicheng Yang, MD, PhD, Carter Suryadevara, and Tony Shan for their contribution on data discussion.

Conflict of interest

All other authors do not have any conflict of interest.

Supplementary material

262_2013_1405_MOESM1_ESM.pdf (86 kb)
Supplementary material 1 (PDF 86 kb)

References

  1. 1.
    Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, Hwang LN, Yu Z, Wrzesinski C, Heimann DM, Surh CD, Rosenberg SA, Restifo NP (2005) Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8 + T cells. J Exp Med 202(7):907–912. doi: 10.1084/jem.20050732 PubMedCrossRefGoogle Scholar
  2. 2.
    Gattinoni L, Powell DJ Jr, Rosenberg SA, Restifo NP (2006) Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol 6(5):383–393. doi: 10.1038/nri1842 PubMedCrossRefGoogle Scholar
  3. 3.
    Cancro MP (2004) The BLyS family of ligands and receptors: an archetype for niche-specific homeostatic regulation. Immunol Rev 202:237–249. doi: 10.1111/j.0105-2896.2004.00212.x PubMedCrossRefGoogle Scholar
  4. 4.
    Gorelik L, Gilbride K, Dobles M, Kalled SL, Zandman D, Scott ML (2003) Normal B cell homeostasis requires B cell activation factor production by radiation-resistant cells. J Exp Med 198(6):937–945. doi: 10.1084/jem.20030789 PubMedCrossRefGoogle Scholar
  5. 5.
    Woodland RT, Schmidt MR, Thompson CB (2006) BLyS and B cell homeostasis. Semin Immunol 18(5):318–326. doi: 10.1016/j.smim.2006.06.001 PubMedCrossRefGoogle Scholar
  6. 6.
    Bosello S, Youinou P, Daridon C, Tolusso B, Bendaoud B, Pietrapertosa D, Morelli A, Ferraccioli G (2008) Concentrations of BAFF correlate with autoantibody levels, clinical disease activity, and response to treatment in early rheumatoid arthritis. J Rheumatol 35(7):1256–1264. doi: 08/13/061 PubMedGoogle Scholar
  7. 7.
    Gor DO, Ding X, Li Q, Sultana D, Mambula SS, Bram RJ, Greenspan NS (2011) Enhanced immunogenicity of pneumococcal surface adhesin A (PsaA) in mice via fusion to recombinant human B lymphocyte stimulator (BLyS). Biol Direct 6:9. doi: 10.1186/1745-6150-6-9 PubMedCrossRefGoogle Scholar
  8. 8.
    Dosenovic P, Soldemo M, Scholz JL, O’Dell S, Grasset EK, Pelletier N, Karlsson MC, Mascola JR, Wyatt RT, Cancro MP, Karlsson Hedestam GB (2012) BLyS-mediated modulation of naive B cell subsets impacts HIV Env-induced antibody responses. J Immunol 188(12):6018–6026. doi: 10.4049/jimmunol.1200466 PubMedCrossRefGoogle Scholar
  9. 9.
    Mackay F, Schneider P (2009) Cracking the BAFF code. Nat Rev Immunol 9(7):491–502. doi: 10.1038/nri2572 PubMedCrossRefGoogle Scholar
  10. 10.
    Mackay F, Browning JL (2002) BAFF: a fundamental survival factor for B cells. Nat Rev Immunol 2(7):465–475. doi: 10.1038/nri844 PubMedCrossRefGoogle Scholar
  11. 11.
    Scapini P, Carletto A, Nardelli B, Calzetti F, Roschke V, Merigo F, Tamassia N, Pieropan S, Biasi D, Sbarbati A, Sozzani S, Bambara L, Cassatella MA (2005) Proinflammatory mediators elicit secretion of the intracellular B-lymphocyte stimulator pool (BLyS) that is stored in activated neutrophils: implications for inflammatory diseases. Blood 105(2):830–837. doi: 10.1182/blood-2004-02-0564 PubMedCrossRefGoogle Scholar
  12. 12.
    Scapini P, Nardelli B, Nadali G, Calzetti F, Pizzolo G, Montecucco C, Cassatella MA (2003) G-CSF-stimulated neutrophils are a prominent source of functional BLyS. J Exp Med 197(3):297–302PubMedCrossRefGoogle Scholar
  13. 13.
    Kreuzaler M, Rauch M, Salzer U, Birmelin J, Rizzi M, Grimbacher B, Plebani A, Lougaris V, Quinti I, Thon V, Litzman J, Schlesier M, Warnatz K, Thiel J, Rolink AG, Eibel H (2012) Soluble BAFF levels inversely correlate with peripheral B cell numbers and the expression of BAFF receptors. J Immunol 188(1):497–503. doi: 10.4049/jimmunol.1102321 PubMedCrossRefGoogle Scholar
  14. 14.
    Schneider P, Tschopp J (2003) BAFF and the regulation of B cell survival. Immunol Lett 88(1):57–62PubMedCrossRefGoogle Scholar
  15. 15.
    Crowley JE, Treml LS, Stadanlick JE, Carpenter E, Cancro MP (2005) Homeostatic niche specification among naive and activated B cells: a growing role for the BLyS family of receptors and ligands. Semin Immunol 17(3):193–199. doi: 10.1016/j.smim.2005.02.001 PubMedCrossRefGoogle Scholar
  16. 16.
    Waldschmidt TJ, Noelle RJ (2001) Immunology. Long live the mature B cell–a baffling mystery resolved. Science 293(5537):2012–2013. doi: 10.1126/science.1065591 PubMedCrossRefGoogle Scholar
  17. 17.
    Schiemann B, Gommerman JL, Vora K, Cachero TG, Shulga-Morskaya S, Dobles M, Frew E, Scott ML (2001) An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 293(5537):2111–2114. doi: 10.1126/science.1061964 PubMedCrossRefGoogle Scholar
  18. 18.
    Cassani B, Poliani PL, Marrella V, Schena F, Sauer AV, Ravanini M, Strina D, Busse CE, Regenass S, Wardemann H, Martini A, Facchetti F, van der Burg M, Rolink AG, Vezzoni P, Grassi F, Traggiai E, Villa A (2010) Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome. J Exp Med 207(7):1525–1540. doi: 10.1084/jem.20091928 PubMedCrossRefGoogle Scholar
  19. 19.
    Walter JE, Rucci F, Patrizi L, Recher M, Regenass S, Paganini T, Keszei M, Pessach I, Lang PA, Poliani PL, Giliani S, Al-Herz W, Cowan MJ, Puck JM, Bleesing J, Niehues T, Schuetz C, Malech H, DeRavin SS, Facchetti F, Gennery AR, Andersson E, Kamani NR, Sekiguchi J, Alenezi HM, Chinen J, Dbaibo G, ElGhazali G, Fontana A, Pasic S, Detre C, Terhorst C, Alt FW, Notarangelo LD (2010) Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency. J Exp Med 207(7):1541–1554. doi: 10.1084/jem.20091927 PubMedCrossRefGoogle Scholar
  20. 20.
    Crowley JE, Scholz JL, Quinn WJ III, Stadanlick JE, Treml JF, Treml LS, Hao Y, Goenka R, O’Neill PJ, Matthews AH, Parsons RF, Cancro MP (2008) Homeostatic control of B lymphocyte subsets. Immunol Res 42(1–3):75–83. doi: 10.1007/s12026-008-8036-y PubMedCrossRefGoogle Scholar
  21. 21.
    Treml LS, Crowley JE, Cancro MP (2006) BLyS receptor signatures resolve homeostatically independent compartments among naive and antigen-experienced B cells. Semin Immunol 18(5):297–304. doi: 10.1016/j.smim.2006.07.001 PubMedCrossRefGoogle Scholar
  22. 22.
    Sampson JH, Aldape KD, Archer GE, Coan A, Desjardins A, Friedman AH, Friedman HS, Gilbert MR, Herndon JE, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling R, Shi W, Vredenburgh JJ, Bigner DD, Heimberger AB (2011) Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol 13(3):324–333. doi: 10.1093/neuonc/noq157 PubMedCrossRefGoogle Scholar
  23. 23.
    Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, Gilbert MR, Herndon JE II, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling RJ, Shi W, Vredenburgh JJ, Bigner DD (2010) Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol 28(31):4722–4729. doi: 10.1200/JCO.2010.28.6963 PubMedCrossRefGoogle Scholar
  24. 24.
    Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Herndon JE II, Lally-Goss D, McGehee-Norman S, Paolino A, Reardon DA, Friedman AH, Friedman HS, Bigner DD (2009) An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme. Mol Cancer Ther 8(10):2773–2779. doi: 10.1158/1535-7163.MCT-09-0124 PubMedCrossRefGoogle Scholar
  25. 25.
    Neyns B, Tosoni A, Hwu WJ, Reardon DA (2010) Dose-dense temozolomide regimens: antitumor activity, toxicity, and immunomodulatory effects. Cancer 116(12):2868–2877. doi: 10.1002/cncr.25035 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Luis Sanchez-Perez
    • 1
    • 2
  • Bryan D. Choi
    • 1
    • 3
  • Elizabeth A. Reap
    • 1
    • 2
  • Elias J. Sayour
    • 1
    • 3
  • Pamela Norberg
    • 1
  • Robert J. Schmittling
    • 1
  • Gerald E. Archer
    • 1
    • 2
  • James E. Herndon2nd
    • 6
  • Duane A. Mitchell
    • 1
    • 2
  • Amy B. Heimberger
    • 7
  • Darell D. Bigner
    • 1
    • 2
  • John H. Sampson
    • 1
    • 2
    • 3
    • 4
    • 5
    Email author
  1. 1.Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of SurgeryDuke University Medical CenterDurhamUSA
  2. 2.The Preston Robert Tisch Brain Tumor Center at DukeDuke University Medical CenterDurhamUSA
  3. 3.Department of PathologyDuke University Medical CenterDurhamUSA
  4. 4.Department of Radiation OncologyDuke University Medical CenterDurhamUSA
  5. 5.Department of ImmunologyDuke University Medical CenterDurhamUSA
  6. 6.Department of Biostatistics and BioinformaticsDuke University Medical CenterDurhamUSA
  7. 7.Department of Neurosurgery, Unit 442The University of Texas MD Anderson Cancer CenterHoustonUSA

Personalised recommendations