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Novel Immunologic Approaches in Lymphoma: Unleashing the Brakes on the Immune System

  • Lymphomas (PA Hamlin, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Immunotherapy is a promising therapeutic strategy in the treatment of lymphoma. The programmed death-1 (PD-1)/PD-ligand immune checkpoint pathway has been manipulated by tumor cells and serves as a mechanism of tumor evasion from the anti-tumor immune response. The recent development of anti-PD-1 antibodies has offered a therapeutic strategy for restoring the function of exhausted antigen-specific T cells and enhancing the endogenous anti-tumor immunity. We review the clinical studies demonstrating efficacy and safety of PD-1 antibodies in relapsed/refractory Hodgkin, follicular, and diffuse large B cell lymphoma. Principles learned in the development of immune checkpoint blockade provide the foundation for immunotherapy under clinical investigation.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Sato E, Olson SH, Ahn J, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A. 2005;102:18538–43.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Clemente CG, Mihm Jr MC, Bufalino R, et al. Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer. 1996;77:1303–10.

    Article  CAS  PubMed  Google Scholar 

  3. Loi S, Sirtaine N, Piette F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02–98. J Clin Oncol. 2013;31:860–7.

    Article  CAS  PubMed  Google Scholar 

  4. Rosenberg SA, Fox E, Churchill WH. Spontaneous regression of hepatic metastases from gastric carcinoma. Cancer. 1972;29:472–4.

    Article  CAS  PubMed  Google Scholar 

  5. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4.

    Article  CAS  PubMed  Google Scholar 

  6. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.

    Article  CAS  PubMed  Google Scholar 

  7. Okazaki T, Chikuma S, Iwai Y, et al. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol. 2013;14:1212–8.

    Article  CAS  PubMed  Google Scholar 

  8. Okazaki T, Honjo T. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol. 2006;27:195–201.

    Article  CAS  PubMed  Google Scholar 

  9. Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12:492–9.

    Article  CAS  PubMed  Google Scholar 

  10. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8:467–77.

    Article  CAS  PubMed  Google Scholar 

  11. Carreras J, Lopez-Guillermo A, Roncador G, et al. High numbers of tumor-infiltrating programmed cell death 1-positive regulatory lymphocytes are associated with improved overall survival in follicular lymphoma. J Clin Oncol. 2009;27:1470–6.

    Article  PubMed  Google Scholar 

  12. Tzankov A, Meier C, Hirschmann P, et al. Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin’s lymphoma. Haematologica. 2008;93:193–200.

    Article  CAS  PubMed  Google Scholar 

  13. Muenst S, Hoeller S, Dirnhofer S, Tzankov A. Increased programmed death-1+ tumor-infiltrating lymphocytes in classical Hodgkin lymphoma substantiate reduced overall survival. Hum Pathol. 2009;40:1715–22.

    Article  CAS  PubMed  Google Scholar 

  14. Intlekofer AM, Thompson CB. At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. J Leukoc Biol. 2013;94:25–39.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Yang ZZ, Novak AJ, Stenson MJ, et al. Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma. Blood. 2006;107:3639–46.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Myklebust JH, Irish JM, Brody J, et al. High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells. Blood. 2013;121:1367–76.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116:3268–77.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Steidl C, Shah SP, Woolcock BW, et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature. 2011;471:377–81.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Green MR, Rodig S, Juszczynski P, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res. 2012;18:1611–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311–9. This phase 1 study reported an 87 % overall response rate with nivolumab (anti-PD-1) in heavily pre-treated relapsed or refractory HL patients leading to FDA approval for Breakthrough Therapy Designation for patients who have failed autologous stem cell transplant and brentuximab therapy.

    Article  CAS  PubMed  Google Scholar 

  21. Moskowitz CH, Ribrag, V, Michot, J, et al. (2014) PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: preliminary results from a phase 1b study (KEYNOTE-013). Blood. ASH 2014 Abstracts, Session 624; Abstract:290 2014.

  22. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. 2004;22:329–60.

    Article  CAS  PubMed  Google Scholar 

  23. Lee ST, Liu S, Radvanyi L, et al. A novel strategy for rapid and efficient isolation of human tumor-specific CD4(+) and CD8(+) T-cell clones. J Immunol Methods. 2008;331:13–26.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Dave SS, Wright G, Tan B, et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med. 2004;351:2159–69.

    Article  CAS  PubMed  Google Scholar 

  25. Alvaro T, Lejeune M, Salvado MT, et al. Immunohistochemical patterns of reactive microenvironment are associated with clinicobiologic behavior in follicular lymphoma patients. J Clin Oncol. 2006;24:5350–7.

    Article  PubMed  Google Scholar 

  26. Berger R, Rotem-Yehudar R, Slama G, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14:3044–51.

    Article  CAS  PubMed  Google Scholar 

  27. Westin JR, Chu F, Zhang M, et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol. 2014;15:69–77. This is a phase 2 study reported on the efficacy and safety of pidilizumab (anti-PD-1) in combination with rituximab in relapsed FL. Two-thirds of patients responded, with the majority of responses consisting of a CR (52 %). Correlate work supports the rationale of targeting the endogenous anti-tumor immunity in FL and suggests synergy with agents like rituximab which may enhance NK-mediated immunity.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Andorsky DJ, Yamada RE, Said J, et al. Programmed death ligand 1 is expressed by non-Hodgkin lymphomas and inhibits the activity of tumor-associated T cells. Clin Cancer Res. 2011;17:4232–44.

    Article  CAS  PubMed  Google Scholar 

  29. Li Y, Wang J, Li C, Ke XY. Contribution of PD-L1 to oncogenesis of lymphoma and its RNAi-based targeting therapy. Leuk Lymphoma. 2012;53:2015–23.

    Article  CAS  PubMed  Google Scholar 

  30. Chen BJ, Chapuy B, Ouyang J, et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res. 2013;19:3462–73.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Rossille D, Gressier M, Damotte D, et al. High level of soluble programmed cell death ligand 1 in blood impacts overall survival in aggressive diffuse large B-Cell lymphoma: results from a French multicenter clinical trial. Leukemia. 2014;28:2367–75.

    Article  CAS  PubMed  Google Scholar 

  32. Ansell SM, Stenson M, Habermann TM, et al. Cd4+ T-cell immune response to large B-cell non-Hodgkin’s lymphoma predicts patient outcome. J Clin Oncol. 2001;19:720–6.

    CAS  PubMed  Google Scholar 

  33. Guillaume T, Rubinstein DB, Symann M. Immune reconstitution and immunotherapy after autologous hematopoietic stem cell transplantation. Blood. 1998;92:1471–90.

    CAS  PubMed  Google Scholar 

  34. Armand P, Nagler A, Weller EA, et al. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J Clin Oncol. 2013;31:4199–206.

    Article  CAS  PubMed  Google Scholar 

  35. Lesokhin AM, Ansell SM, Armand P, et al. (2014) Preliminary results of a phase I study of nivolumab (BMS-936558) in patients with relapsed or refractory lymphoid malignancies. Blood. ASH 2014 Abstracts, Session 624; Abstract:291 2014.

  36. Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124:687–95.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:925–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Golden EB, Demaria S, Schiff PB, et al. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res. 2013;1:365–72.

    Article  PubMed Central  PubMed  Google Scholar 

  39. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122–33.

    Article  CAS  PubMed  Google Scholar 

  40. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–26.

    Article  CAS  PubMed  Google Scholar 

  42. Wolchok JD, Weber JS, Maio M, et al. Four-year survival rates for patients with metastatic melanoma who received ipilimumab in phase II clinical trials. Ann Oncol. 2013;24:2174–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Prieto PA, Yang JC, Sherry RM, et al. CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res. 2012;18:2039–47.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Schadendorf D, Hodi FS, Robert C et al. (2015) Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 2015.

  45. Hodi FS, Lawrence D, Lezcano C, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res. 2014;2:632–42.

    Article  CAS  PubMed  Google Scholar 

  46. Ribas A, Hodi FS, Callahan M, et al. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368:1365–6.

    Article  CAS  PubMed  Google Scholar 

  47. O’Mahony D, Morris JC, Quinn C, et al. A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy. Clin Cancer Res. 2007;13:958–64.

    Article  PubMed  Google Scholar 

  48. Ansell SM, Hurvitz SA, Koenig PA, et al. Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res. 2009;15:6446–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Houot R, Goldstein MJ, Kohrt HE, et al. Therapeutic effect of CD137 immunomodulation in lymphoma and its enhancement by Treg depletion. Blood. 2009;114:3431–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Kohrt HE, Houot R, Goldstein MJ, et al. CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies. Blood. 2011;117:2423–32.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Triebel F, Jitsukawa S, Baixeras E, et al. LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med. 1990;171:1393–405.

    Article  CAS  PubMed  Google Scholar 

  52. Workman CJ, Vignali DA. Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223). J Immunol. 2005;174:688–95.

    Article  CAS  PubMed  Google Scholar 

  53. Gandhi MK, Lambley E, Duraiswamy J, et al. Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8+ T-cell function in Hodgkin lymphoma patients. Blood. 2006;108:2280–9.

    Article  CAS  PubMed  Google Scholar 

  54. Zhang J, Xiang Y, Ding L, et al. Using gene co-expression network analysis to predict biomarkers for chronic lymphocytic leukemia. BMC Bioinf. 2010;11 Suppl 9:S5.

    Article  Google Scholar 

  55. Kotaskova J, Tichy B, Trbusek M, et al. High expression of lymphocyte-activation gene 3 (LAG3) in chronic lymphocytic leukemia cells is associated with unmutated immunoglobulin variable heavy chain region (IGHV) gene and reduced treatment-free survival. J Mol Diagn. 2010;12:328–34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from the National Institutes of Health R01 CA155143 (SSN), the Leukemia and Lymphoma Society P-QFC-3068-14 (SSN), and the Cancer Prevention and Research Institute of Texas RP150318 (SSN). We thank Mark Nastoupil for assistance with the illustration.

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Conflict of Interest

Loretta J. Nastoupil has received compensation from Celgene and Genentech for service as a consultant.

Sattva S. Neelapu has received research support from Bristol-Myers Squibb, CureTech, Celegene, and Merck, and has received compensation from Celgene for service as a consultant.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429, Houston, TX, 77030, USA

    Loretta J. Nastoupil & Sattva S. Neelapu

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  1. Loretta J. Nastoupil
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  2. Sattva S. Neelapu
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Correspondence to Sattva S. Neelapu.

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This article is part of the Topical Collection on Lymphomas

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Nastoupil, L.J., Neelapu, S.S. Novel Immunologic Approaches in Lymphoma: Unleashing the Brakes on the Immune System. Curr Oncol Rep 17, 30 (2015). https://doi.org/10.1007/s11912-015-0456-y

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