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Cancer Immunology, Immunotherapy

, Volume 61, Issue 10, pp 1819–1832 | Cite as

Optimized adoptive T-cell therapy for the treatment of residual mantle cell lymphoma

  • Corey M. Munger
  • Ganapati V. Hegde
  • Dennis D. Weisenburger
  • Julie M. Vose
  • Shantaram S. JoshiEmail author
Original article

Abstract

Mantle cell lymphoma (MCL) is an aggressive B-cell neoplasm with few patients achieving long-term survival with current treatment regimens. High-dose therapy is effective in reducing the tumor burden; however, patients eventually relapse due to minimal residual disease. Having demonstrated efficacy in other malignancies, the effectiveness of dendritic cell-based immunotherapy for minimal residual MCL was examined. We demonstrated that dendritic cells (DC) primed with MCL antigens stimulated the activation of MCL-specific T cells that recognized and destroyed both MCL cell lines and primary MCL in vitro. In addition, in vivo studies demonstrated that adoptively transferred MCL-specific T cells were able to significantly inhibit tumor growth in mice with minimal residual MCL. Subsequently, when combined with CHOP chemotherapy, adoptive T-cell therapy was able to significantly extend the survival of the mice by further reducing the tumor burden. These results clearly show that MCL-specific cellular immunotherapy is effective in treating minimal residual MCL, paving the way for future clinical studies.

Keywords

Dendritic cells Mantle cell lymphoma Minimal residual tumor Immunotherapy Adoptive T-cell transfer 

Notes

Acknowledgments

This work was funded by The Lymphoma Research Foundation, New York, NY. We would like to thank Dr. Gordon Todd and Dr. Charles Kuszynski for their help in virtual microscopy and apheresis. We wish to thank Mrs. Kathryn Hyde for her secretarial help during the study.

Supplementary material

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Supplementary material 1 (JPEG 2260 kb)

References

  1. 1.
    Weisenburger DD, Armitage JO (1996) Mantle cell lymphoma: an entity comes of age. Blood 87:4483–4494PubMedGoogle Scholar
  2. 2.
    Campo E, Raffeld M, Jaffe ES (1999) Mantle-cell lymphoma. Semin Hematol 36:115–127PubMedGoogle Scholar
  3. 3.
    Swerdlow SH, Williams ME (2002) From centrocytic to mantle cell lymphoma: a clinicopathologic and molecular review of 3 decades. Hum Pathol 33:7–20PubMedCrossRefGoogle Scholar
  4. 4.
    Dreyling M, Hiddemann W (2009) European MCL Network. Current treatment standards and emerging strategies in mantle cell lymphoma. Hematology Am Soc Hematol Educ Program 2009(1):542–551Google Scholar
  5. 5.
    Koch M, Beckhove P, Op den Winkel J et al (2006) Tumor infiltrating T lymphocytes in colorectal cancer: Tumor-selective activation and cytotoxic activity in situ. Ann Surg 244:986–992 discussion 992-3PubMedCrossRefGoogle Scholar
  6. 6.
    Liakou CI, Narayanan S, Ng Tang D, Logothetis CJ, Sharma P (2007) Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human bladder cancer. Cancer Immun 7:10PubMedGoogle Scholar
  7. 7.
    Yu P, Fu YX (2006) Tumor-infiltrating T lymphocytes: friends or foes? Lab Invest 86:231–245PubMedCrossRefGoogle Scholar
  8. 8.
    Mackensen A, Meidenbauer N, Vogl S, Laumer M, Berger J, Andreesen R (2006) Phase I study of adoptive T-cell therapy using antigen-specific CD8+ T cells for the treatment of patients with metastatic melanoma. J Clin Oncol 24:5060–5069PubMedCrossRefGoogle Scholar
  9. 9.
    Meidenbauer N, Marienhagen J, Laumer M et al (2003) Survival and tumor localization of adoptively transferred Melan-A-specific T cells in melanoma patients. J Immunol 170:2161–2169PubMedGoogle Scholar
  10. 10.
    Marijt E, Wafelman A, van der Hoorn M et al (2007) Phase I/II feasibility study evaluating the generation of leukemia-reactive cytotoxic T lymphocyte lines for treatment of patients with relapsed leukemia after allogeneic stem cell transplantation. Haematologica 92:72–80PubMedCrossRefGoogle Scholar
  11. 11.
    Till BG, Jensen MC, Wang J et al (2008) Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 112:2261–2271PubMedCrossRefGoogle Scholar
  12. 12.
    Kapp M, Stevanovic S, Fick K et al (2009) CD8+ T-cell responses to tumor-associated antigens correlate with superior relapse-free survival after allo-SCT. Bone Marrow Transplant 43:399–410PubMedCrossRefGoogle Scholar
  13. 13.
    Ringden O, Karlsson H, Olsson R, Omazic B, Uhlin M (2009) The allogeneic graft-versus-cancer effect. Br J Haematol 147:614–633PubMedCrossRefGoogle Scholar
  14. 14.
    Robson NC, Hoves S, Maraskovsky E, Schnurr M (2010) Presentation of tumour antigens by dendritic cells and challenges faced. Curr Opin Immunol 22:137–144PubMedCrossRefGoogle Scholar
  15. 15.
    Scott-Taylor TH, Pettengell R, Clarke I et al (2000) Human tumour and dendritic cell hybrids generated by electrofusion: potential for cancer vaccines. Biochim Biophys Acta 1500:265–279PubMedCrossRefGoogle Scholar
  16. 16.
    Tucker CA, Bebb G, Klasa RJ et al (2006) Four human t(11;14)(q13;q32)-containing cell lines having classic and variant features of mantle cell lymphoma. Leuk Res 30:449–457PubMedCrossRefGoogle Scholar
  17. 17.
    Milazzo C, Reichardt VL, Muller MR, Grunebach F, Brossart P (2003) Induction of myeloma-specific cytotoxic T cells using dendritic cells transfected with tumor-derived RNA. Blood 101:977–982PubMedCrossRefGoogle Scholar
  18. 18.
    Munger CM, Vose JM, Joshi SS (2006) Dendritic cell-based therapy for mantle cell lymphoma. Int J Oncol 28:1337–1343PubMedGoogle Scholar
  19. 19.
    Yu Z, Ma B, Zhou Y, et al (2007) Allogeneic tumor vaccine produced by electrofusion between osteosarcoma cell line and dendritic cells in the induction of antitumor immunity. Cancer Invest 25:535–541Google Scholar
  20. 20.
    Koido S, Tanaka Y, Tajiri H, Gong J (2007) Generation and functional assessment of antigen-specific T cells stimulated by fusions of dendritic cells and allogeneic breast cancer cells. Vaccine 25:2610–2619PubMedCrossRefGoogle Scholar
  21. 21.
    Kennedy R, Celis E (2008) Multiple roles for CD4+ T cells in anti-tumor immune responses. Immunol Rev 222:129–144PubMedCrossRefGoogle Scholar
  22. 22.
    Singh H, Serrano LM, Pfeiffer T et al (2007) Combining adoptive cellular and immunocytokine therapies to improve treatment of B-lineage malignancy. Cancer Res 67:2872–2880PubMedCrossRefGoogle Scholar
  23. 23.
    Kowolik CM, Topp MS, Gonzalez S et al (2006) CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res 66:10995–11004PubMedCrossRefGoogle Scholar
  24. 24.
    Winter H, Hu HM, Poehlein CH et al (2003) Tumour-induced polarization of tumour vaccine-draining lymph node T cells to a type 1 cytokine profile predicts inherent strong immunogenicity of the tumour and correlates with therapeutic efficacy in adoptive transfer studies. Immunology 108:409–419PubMedCrossRefGoogle Scholar
  25. 25.
    Kondo T, Nakazawa H, Ito F et al (2006) Favorable prognosis of renal cell carcinoma with increased expression of chemokines associated with a Th1-type immune response. Cancer Sci 97:780–786PubMedCrossRefGoogle Scholar
  26. 26.
    Anasetti C, Mule JJ (2007) To ablate or not to ablate? HSCs in the T cell driver’s seat. J Clin Invest 117:306–310PubMedCrossRefGoogle Scholar
  27. 27.
    Gattinoni L, Finkelstein SE, Klebanoff CA et al (2005) Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med 202:907–912PubMedCrossRefGoogle Scholar
  28. 28.
    Muranski P, Boni A, Wrzesinski C et al (2006) Increased intensity lymphodepletion and adoptive immunotherapy–how far can we go? Nat Clin Pract Oncol 3:668–681PubMedCrossRefGoogle Scholar
  29. 29.
    Jenq RR, van den Brink MR (2010) Allogeneic haematopoietic stem cell transplantation: individualized stem cell and immune therapy of cancer. Nat Rev Cancer 10:213–221PubMedCrossRefGoogle Scholar
  30. 30.
    Maine GN, Mule JJ (2002) Making room for T cells. J Clin Invest 110:157–159PubMedGoogle Scholar
  31. 31.
    Fry TJ, Mackall CL (2001) Interleukin-7: master regulator of peripheral T-cell homeostasis? Trends Immunol 22:564–571PubMedCrossRefGoogle Scholar
  32. 32.
    Dudley ME, Wunderlich JR, Yang JC et al (2005) Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 23:2346–2357PubMedCrossRefGoogle Scholar
  33. 33.
    Asavaroengchai W, Kotera Y, Mule JJ (2002) Tumor lysate-pulsed dendritic cells can elicit an effective antitumor immune response during early lymphoid recovery. Proc Natl Acad Sci USA 99:931–936PubMedCrossRefGoogle Scholar
  34. 34.
    Wrzesinski C, Paulos CM, Gattinoni L et al (2007) Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8 T cells. J Clin Invest 117:492–501PubMedCrossRefGoogle Scholar
  35. 35.
    Martinez A, Bellosillo B, Bosch F et al (2004) Nuclear survivin expression in mantle cell lymphoma is associated with cell proliferation and survival. Am J Pathol 164:501–510PubMedCrossRefGoogle Scholar
  36. 36.
    Amin HM, McDonnell TJ, Medeiros LJ et al (2003) Characterization of 4 mantle cell lymphoma cell lines. Arch Pathol Lab Med 127:424–431PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Corey M. Munger
    • 1
  • Ganapati V. Hegde
    • 1
  • Dennis D. Weisenburger
    • 2
  • Julie M. Vose
    • 3
  • Shantaram S. Joshi
    • 1
    Email author
  1. 1.Department of Genetics, Cell Biology and Anatomy, Center for Research in Leukemia and LymphomaUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.Department of Pathology and Microbiology, Center for Research in Leukemia and LymphomaUniversity of Nebraska Medical CenterOmahaUSA
  3. 3.Department of Internal Medicine-Section of Oncology and Hematology, Center for Research in Leukemia and LymphomaUniversity of Nebraska Medical CenterOmahaUSA

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