Skip to main content
Latest news
Browse specialties
Breast cancer Genitourinary cancers Lung & thoracic cancers
In focus
Next-generation sequencing: Emerging biomarkers in thyroid and NSCLCs ctDNA and bladder cancer: Current understanding and beyond ROS1 fusion-positive NSCLC NSCLC driver mutations: Discussing the importance of RET, ALK and ROS1 alterations in NSCLC Early-stage NSCLC management: Surgery, targeted treatment and immunotherapy ALK fusion-positive NSCLC: International approaches to management RET fusion-positive NSCLC: Informing on the use of pralsetinib for patients with RET fusion-positive, advanced NSCLC COVID-19 & cancer
Conferences
SABCS 2022 ESMO 2022 2022 ASCO Annual Meeting
About us
Medicine Matters Oncology
EXTENDED SEARCH
Top

03-11-2015 | Hematologic cancers | Article

Novel immunotherapies in lymphoid malignancies

Authors: Connie Lee Batlevi, Eri Matsuki, Renier J. Brentjens, Anas Younes

Login to get access

Abstract

The success of the anti-CD20 monoclonal antibody rituximab in the treatment of lymphoid malignancies provided proof-of-principle for exploiting the immune system therapeutically. Since the FDA approval of rituximab in 1997, several novel strategies that harness the ability of T cells to target cancer cells have emerged. Reflecting on the promising clinical efficacy of these novel immunotherapy approaches, the FDA has recently granted 'breakthrough' designation to three novel treatments with distinct mechanisms. First, chimeric antigen receptor (CAR)-T-cell therapy is promising for the treatment of adult and paediatric relapsed and/or refractory acute lymphoblastic leukaemia (ALL). Second, blinatumomab, a bispecific T-cell engager (BiTE®) antibody, is now approved for the treatment of adults with Philadelphia-chromosome-negative relapsed and/or refractory B-precursor ALL. Finally, the monoclonal antibody nivolumab, which targets the PD-1 immune-checkpoint receptor with high affinity, is used for the treatment of Hodgkin lymphoma following treatment failure with autologous-stem-cell transplantation and brentuximab vedotin. Herein, we review the background and development of these three distinct immunotherapy platforms, address the scientific advances in understanding the mechanism of action of each therapy, and assess the current clinical knowledge of their efficacy and safety. We also discuss future strategies to improve these immunotherapies through enhanced engineering, biomarker selection, and mechanism-based combination regimens.

Nat Rev Clin Oncol 2016; 13: 25–40. doi:10.1038/nrclinonc.2015.187

Subject terms: Cancer immunotherapy • Lymphoma

The concept of immunotherapy for treating cancer emerged almost a century ago; the graft-versus-tumour effect following allogeneic haematopoietic-stem-cell transplantation (HSCT) was one of the first examples of immunotherapy.1 Furthermore, the success of rituximab in treating lymphoid malignancies provided proof-of-principle for exploiting the immune system in a target-specific manner.2, 3, 4 With improved technology and a better understanding of immune-regulatory mechanisms, cancer immunotherapy is rapidly evolving to exploit the therapeutic value of activating autologous T cells.

Literature
  1. Horowitz, M. et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75, 555–562 (1990). CAS | ISI | PubMed
  2. Maloney, D. G. et al. IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J. Clin. Oncol. 15, 3266–3274 (1997). CAS | ISI | PubMed
  3. Maloney, D. G. et al. IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood 90, 2188–2195 (1997). CAS | ISI | PubMed
  4. Coiffier, B. et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N. Engl. J. Med. 346, 235–242 (2002). CAS | ISI | PubMed | Article
  5. Doubrovina, E. et al. Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation. Blood119, 2644–2656 (2012). CAS | ISI | PubMed | Article
  6. Chapuis, A. G. et al. Transferred WT1-reactive CD8+ T cells can mediate antileukemic activity and persist in post-transplant patients. Sci. Transl. Med. 5, 174ra27 (2013). CAS | PubMed | Article |
  7. Rooney, C. M. et al. Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood 92, 1549–1555 (1998). CAS | ISI | PubMed
  8. Heslop, H. E. et al. Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood 115, 925–935 (2010). CAS | ISI | PubMed | Article
  9. Bollard, C. M. et al. Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J. Clin. Oncol. 32, 798–808 (2014). CAS | ISI | PubMed | Article
  10. Eshhar, Z., Waks, T., Gross, G. & Schindler, D. G. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the γ or ζ subunits of the immunoglobulin and T-cell receptors. Proc. Natl Acad. Sci. USA 90, 720–724 (1993). CAS | PubMed | Article
  11. Annenkov, A. E., Moyes, S. P., Eshhar, Z., Mageed, R. A. & Chernajovsky, Y. Loss of original antigenic specificity in T cell hybridomas transduced with a chimeric receptor containing single-chain Fv of an anti-collagen antibody and FcεRI-signaling γ subunit. J. Immunol.161, 6604–6613 (1998). CAS | ISI | PubMed
  12. Haynes, N. M. et al. Redirecting mouse CTL against colon carcinoma: superior signaling efficacy of single-chain variable domain chimeras containing TCR-ζ vs FcεRI-γ. J. Immunol.166, 182–187 (2001). CAS | ISI | PubMed | Article
  13. Gross, G., Waks, T. & Eshhar, Z. Expression of immunoglobulin–T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc. Natl Acad. Sci. USA86, 10024–10028 (1989). CAS | PubMed | Article
  14. Bird, R. E. et al. Single-chain antigen-binding proteins. Science 242, 423–426 (1988). CAS | ISI | PubMed | Article
  15. Huston, J. S. et al. Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in Escherichia coli. Proc. Natl Acad. Sci. USA 85, 5879–5883 (1988). CAS | PubMed | Article
  16. Orlandi, R., Gussow, D. H., Jones, P. T. & Winter, G. Cloning immunoglobulin variable domains for expression by the polymerase chain reaction. Proc. Natl Acad. Sci. USA 86, 3833–3837 (1989). CAS | PubMed | Article
  17. Hollyman, D. et al. Manufacturing validation of biologically functional T cells targeted to CD19 antigen for autologous adoptive cell therapy. J. Immunother. 32, 169–180 (2009). CAS | ISI | PubMed | Article
  18. Lee, J., Sadelain, M. & Brentjens, R. Retroviral transduction of murine primary T lymphocytes. Methods Mol. Biol. 506, 83–96 (2009). CAS | PubMed
  19. Quintas-Cardama, A. et al. Multifactorial optimization of gammaretroviral gene transfer into human T lymphocytes for clinical application. Hum. Gene Ther. 18, 1253–1260 (2007). CAS | ISI | PubMed | Article
  20. Brentjens, R. J. et al. Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin. Cancer Res. 13, 5426–5435 (2007). CAS | ISI | PubMed | Article
  21. Brentjens, R. J. et al. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat. Med. 9, 279–286 (2003). CAS | ISI | PubMed | Article
  22. Huang, X. et al. Sleeping Beauty transposon-mediated engineering of human primary T cells for therapy of CD19+ lymphoid malignancies. Mol. Ther. 16, 580–589 (2008). CAS | ISI | PubMed | Article
  23. Kochenderfer, J. N. et al. Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. J. Immunother. 32, 689–702 (2009). CAS | ISI | PubMed | Article
  24. Savoldo, B. et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J. Clin. Invest. 121, 1822–1826 (2011). CAS | ISI | PubMed | Article
  25. Wang, X. et al. Phenotypic and functional attributes of lentivirus-modified CD19-specific human CD8+ central memory T cells manufactured at clinical scale. J. Immunother. 35, 689–701 (2012). CAS | ISI | PubMed | Article
  26. Milone, M. C. et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol. Ther.17, 1453–1464 (2009). CAS | ISI | PubMed | Article
  27. Terakura, S. et al. Generation of CD19-chimeric antigen receptor modified CD8+ T cells derived from virus-specific central memory T cells. Blood 119, 72–82 (2012). CAS | ISI | PubMed | Article
  28. Zola, H. et al. Preparation and characterization of a chimeric CD19 monoclonal antibody. Immunol. Cell Biol. 69, 411–422 (1991). PubMed | Article
  29. Bejcek, B. E. et al. Development and characterization of three recombinant single chain antibody fragments (scFvs) directed against the CD19 antigen. Cancer Res. 55, 2346–2351 (1995). CAS | PubMed
  30. Nicholson, I. C. et al. Construction and characterisation of a functional CD19 specific single chain Fv fragment for immunotherapy of B lineage leukaemia and lymphoma. Mol. Immunol.34, 1157–1165 (1997). CAS | ISI | PubMed | Article
  31. Imai, C. et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 18, 676–684 (2004). CAS | ISI | PubMed | Article
  32. Till, B. G. et al. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 112, 2261–2271 (2008). CAS | ISI | PubMed | Article
  33. Jensen, M. C. et al. Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol. Blood Marrow Transplant. 16, 1245–1256 (2010). CAS | ISI | PubMed | Article
  34. Wang, J. et al. Optimizing adoptive polyclonal T cell immunotherapy of lymphomas, using a chimeric T cell receptor possessing CD28 and CD137 costimulatory domains. Hum. Gene Ther. 18, 712–725 (2007). | CAS | ISI | PubMed | Article
  35. Maher, J., Brentjens, R. J., Gunset, G., Riviere, I. & Sadelain, M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ /CD28 receptor. Nat. Biotechnol. 20, 70–75 (2002). CAS | ISI | PubMed | Article
  36. Hombach, A. A., Rappl, G. & Abken, H. Arming cytokine-induced killer cells with chimeric antigen receptors: CD28 outperforms combined CD28–OX40 “super-stimulation”. Mol. Ther.21, 2268–2277 (2013). CAS | ISI | PubMed | Article
  37. Carpenito, C. et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc. Natl Acad. Sci. USA106, 3360–3365 (2009). PubMed | Article
  38. Zhong, X. S., Matsushita, M., Plotkin, J., Riviere, I. & Sadelain, M. Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication. Mol. Ther. 18, 413–420 (2010). CAS | ISI | PubMed | Article
  39. Tammana, S. et al. 4-1BB and CD28 signaling plays a synergistic role in redirecting umbilical cord blood T cells against B-cell malignancies. Hum. Gene Ther. 21, 75–86 (2010). CAS | ISI | PubMed | Article
  40. Pegram, H. J., Park, J. H. & Brentjens, R. J. CD28z CARs and armored CARs. Cancer J.20, 127–133 (2014). CAS | ISI | PubMed | Article
  41. Jones, B. S., Lamb, L. S., Goldman, F. & Di Stasi, A. Improving the safety of cell therapy products by suicide gene transfer. Front. Pharmacol. 5, 254 (2014). CAS | PubMed | Article
  42. Di Stasi, A. et al. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood 113, 6392–6402 (2009). CAS | ISI | PubMed | Article
  43. Kershaw, M. H. et al. Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2. Hum. Gene Ther. 13, 1971–1980 (2002). CAS | ISI | PubMed | Article
  44. Brentjens, R. J. et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 118, 4817–4828 (2011). CAS | ISI | PubMed | Article
  45. Kalos, M. et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3, 95ra73 (2011). CAS | PubMed | Article
  46. Kochenderfer, J. N. et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood116, 4099–4102 (2010). CAS | ISI | PubMed | Article
  47. Wang, X. & Riviere, I. Manufacture of tumor- and virus-specific T lymphocytes for adoptive cell therapies. Cancer Gene Ther. 22, 85–94 (2015). CAS | PubMed | Article
  48. Brentjens, R. J. et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med. 5, 177ra38 (2013). CAS | PubMed | Article
  49. Davila, M. L. et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6, 224ra25 (2014). CAS | PubMed | Article
  50. Park, J. H. et al. CD19-targeted 19-28z CAR modified autologous T cells induce high rates of complete remission and durable responses in adult patients with relapsed, refractory B-cell ALL [abstract]. Blood 124, a382 (2014).
  51. Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014). CAS | ISI | PubMed | Article
  52. Lee, D. W. et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385, 517–528 (2015). CAS | ISI | PubMed | Article
  53. Fielding, A. K. et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood 109, 944–950 (2007). CAS | ISI | PubMed | Article
  54. Gökbuget, N. et al. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood 120, 2032–2041 (2012). CAS | PubMed | Article
  55. Kantarjian, H. M. et al. Outcome of adults with acute lymphocytic leukemia in second or subsequent complete remission. Leuk. Lymphoma 51, 475–480 (2010). PubMed | Article
  56. Curran, K. J. et al. Validation of donor derived virus specific T-lymphocytes genetically modified to target the CD19 antigen for the treatment of relapsed Leukemia. Mol. Ther. 19, S90 (2011).
  57. Kochenderfer, J. N. et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 122, 4129–4139 (2013). CAS | ISI | PubMed | Article
  58. Park, J. H. et al. Impact of the conditioning chemotherapy on outcomes in adoptive T cell therapy: results from a phase I clinical trial of autologous CD19-targeted T cells for patients with relapsed CLL [abstract]. Blood 120, a1797 (2012). Article
  59. Park, J. H. et al. Phase I trial of autologous CD19-targeted CAR-modified T cells as consolidation after purine analog-based first-line therapy in patients with previously untreated CLL [abstract]. J. Clin. Oncol. 32 (5s Suppl.), a7020 (2014).
  60. Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. & June, C. H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011). CAS | ISI | PubMed | Article
  61. Porter, D. L. et al. Chimeric antigen receptor modified t cells directed against CD19 (CTL019 cells) have long-term persistence and induce durable responses in relapsed, refractory CLL [abstract]. Blood 122, a4162 (2013). Article
  62. Porter, D. L. et al. Randomized, phase II dose optimization study of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed, refractory CLL [abstract]. Blood 124, a1982 (2014).
  63. Kochenderfer, J. N. et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 119, 2709–2720 (2012). CAS | ISI | PubMed | Article
  64. Kochenderfer, J. N. et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J. Clin. Oncol. 33, 540–549 (2015). CAS | PubMed | Article
  65. Kochenderfer, J. N. et al. Anti-CD19 CAR T cells administered after low-dose chemotherapy can induce remissions of chemotherapy-refractory diffuse large B-cell lymphoma [abstract]. Blood 124, a550 (2014).
  66. Schuster, S. J. et al. Phase IIa trial of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas [abstract]. Blood 124, a3087 (2014).
  67. Sauter, C. S. et al. Interim safety analysis: a phase I trial of high dose therapy and autologous stem cell transplantation followed by infusion of chimeric antigen receptor modified T-cells (19-28z CAR-T) directed against CD19+ B-cells for relapsed and refractory aggressive B cell non-Hodgkin lymphoma (B-NHL) [abstract]. Blood 124, a677 (2014). Article
  68. Lee, D. W. et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188–195 (2014). CAS | ISI | PubMed | Article
  69. Maude, S. L., Barrett, D., Teachey, D. T. & Grupp, S. A. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 20, 119–122 (2014). CAS | ISI | PubMed | Article
  70. Ramos, C. A., Savoldo, B. & Dotti, G. CD19-CAR trials. Cancer J. 20, 112–118 (2014). CAS | ISI | PubMed | Article
  71. Maude, S. L., Teachey, D. T., Porter, D. L. & Grupp, S. A. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood 125, 4017–4023 (2015). CAS | PubMed | Article
  72. Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013). CAS | ISI | PubMed | Article
  73. Turtle, C. J. et al. Immunotherapy with CD19-specific chimeric antigen receptor (CAR)-modified T cells of defined subset composition [abstract]. J. Clin. Oncol. 33 (Suppl.), a3006 (2015).
  74. Wang, X. et al. A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells. Blood 118, 1255–1263 (2011). CAS | ISI | PubMed | Article
  75. Di Stasi, A. et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365, 1673–1683 (2011). CAS | ISI | PubMed | Article
  76. Giordano Attianese, G. M. et al. In vitro and in vivo model of a novel immunotherapy approach for chronic lymphocytic leukemia by anti-CD23 chimeric antigen receptor. Blood117, 4736–4745 (2011). CAS | PubMed | Article
  77. Berger, C. et al. Safety of targeting ROR1 in primates with chimeric antigen receptor-modified T cells. Cancer Immunol. Res. 3, 206–216 (2015). CAS | PubMed | Article
  78. Haso, W. et al. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood 121, 1165–1174 (2013). CAS | ISI | PubMed | Article
  79. Vera, J. et al. T lymphocytes redirected against the κ light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells. Blood 108, 3890–3897 (2006). CAS | ISI | PubMed | Article
  80. Savoldo, B. et al. Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-CD30ζ artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease. Blood 110, 2620–2630 (2007). CAS | ISI | PubMed | Article
  81. Ruella, M. et al. Novel chimeric antigen receptor T cells for the treatment of Hodgkin lymphoma [abstract]. Blood 124, a806 (2014).
  82. Chinnasamy, D. et al. Local delivery of interleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice. Clin. Cancer Res. 18, 1672–1683 (2012). CAS | PubMed | Article
  83. Craddock, J. A. et al. Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J. Immunother. 33, 780–788 (2010). CAS | ISI | PubMed | Article
  84. Karlsson, S. C. et al. Combining CAR T cells and the Bcl-2 family apoptosis inhibitor ABT-737 for treating B-cell malignancy. Cancer Gene Ther. 20, 386–393 (2013). CAS | PubMed | Article
  85. Pavel, O. et al. Immunomodulatory agent lenalidomide enhances antitumor functions of chimeric receptor-modified t cells in vitro and in vivo [abstract]. Blood 124, a805 (2014).
  86. John, L. B. et al. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin. Cancer Res. 19, 5636–5646 (2013). CAS | ISI | PubMed | Article
  87. Cruz, C. R. et al. Infusion of donor-derived CD19-redirected-virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase I study [abstract]. Blood 122, a152 (2013). CAS | Article
  88. Turtle, C. J. et al. Therapy of B cell malignancies with CD19-specific chimeric antigen receptor-modified T cells of defined subset composition [abstract]. Blood 124, a384 (2014).
  89. Derniame, S. et al. Multiplex genome editing as a platform for “off-the-shelf” adoptive CAR T-cell immunotherapies [abstract]. Blood 124, a1111 (2014).
  90. Torikai, H. et al. A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR. Blood 119, 5697–5705 (2012). CAS | ISI | PubMed | Article
  91. June, C. H., Riddell, S. R. & Schumacher, T. N. Adoptive cellular therapy: a race to the finish line. Sci. Transl. Med. 7, 280ps7 (2015). CAS | PubMed | Article
  92. Mack, M., Riethmuller, G. & Kufer, P. A small bispecific antibody construct expressed as a functional single-chain molecule with high tumor cell cytotoxicity. Proc. Natl Acad. Sci. USA92, 7021–7025 (1995). CAS | PubMed | Article
  93. Loffler, A. et al. A recombinant bispecific single-chain antibody, CD19 × CD3, induces rapid and high lymphoma-directed cytotoxicity by unstimulated T lymphocytes. Blood 95, 2098–2103 (2000). CAS | ISI | PubMed
  94. Dreier, T. et al. Extremely potent, rapid and costimulation-independent cytotoxic T-cell response against lymphoma cells catalyzed by a single-chain bispecific antibody. Int. J. Cancer 100, 690–697 (2002). CAS | ISI | PubMed | Article
  95. Offner, S., Hofmeister, R., Romaniuk, A., Kufer, P. & Baeuerle, P. A. Induction of regular cytolytic T cell synapses by bispecific single-chain antibody constructs on MHC class I-negative tumor cells. Mol. Immunol. 43, 763–771 (2006). CAS | ISI | PubMed | Article
  96. Schlereth, B. et al. T-cell activation and B-cell depletion in chimpanzees treated with a bispecific anti-CD19/anti-CD3 single-chain antibody construct. Cancer Immunol. Immunother. 55, 503–514 (2006). CAS | ISI | PubMed | Article
  97. Kufer, P. et al. Minimal costimulatory requirements for T cell priming and TH1 differentiation: activation of naive human T lymphocytes by tumor cells armed with bifunctional antibody constructs. Cancer Immun. 1, 10 (2001). CAS | PubMed
  98. Bargou, R. et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 321, 974–977 (2008). CAS | ISI | PubMed | Article
  99. Haas, C. et al. Mode of cytotoxic action of T cell-engaging BiTE antibody MT110. Immunobiology 214, 441–453 (2009). CAS | ISI | PubMed | Article
  100. Gruen, M., Bommert, K. & Bargou, R. C. T-cell-mediated lysis of B cells induced by a CD19 × CD3 bispecific single-chain antibody is perforin dependent and death receptor independent. Cancer Immunol. Immunother. 53, 625–632 (2004). CAS | PubMed | Article
  101. Klinger, M. et al. Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab. Blood 119, 6226–6233 (2012). CAS | ISI | PubMed | Article
  102. Nagorsen, D., Kufer, P., Baeuerle, P. A. & Bargou, R. Blinatumomab: a historical perspective. Pharmacol. Ther. 136, 334–342 (2012). CAS | ISI | PubMed | Article
  103. Goebeler, M. E. et al. Final results from a phase 1 study of blinatumomab in patients with relapsed/refractory non-Hodgkin's lymphoma. Hematol. Oncol. 31, 197 (2013). CAS | PubMed | Article
  104. Swerdlow, S. H. et al. (eds) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 4th edn (International Agency for Research on Cancer, 2008).
  105. Topp, M. S. et al. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood 120, 5185–5187 (2012). CAS | ISI | PubMed | Article
  106. Topp, M. S. et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J. Clin. Oncol. 29, 2493–2498 (2011). CAS | ISI | PubMed | Article
  107. Topp, M. S. et al. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J. Clin. Oncol. 32, 4134–4140 (2014). CAS | ISI |  PubMed | Article
  108. Topp, M. S. et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 16, 57–66 (2015). CAS | PubMed | Article
  109. Viardot, A. et al. Treatment of relapsed/refractory diffuse large B-cell lymphoma with the Bispecific T-cell Engager (BiTE®) antibody construct blinatumomab: primary analysis results from an open-label, phase 2 study [abstract]. Blood 124, a4460 (2014).
  110. Zugmaier, G. et al. Long-term follow-up of serum immunoglobulin levels in blinatumomab-treated patients with minimal residual disease-positive B-precursor acute lymphoblastic leukemia. Blood Cancer J. 4, 244 (2014). CAS | PubMed | Article
  111. Goebeler, M. et al. CD3/CD19 bispecific BiTE antibody blinatumomab treatment of non-Hodgkin lymphoma (NHL) patients: 60 μg/m2/d by continuous infusion is tolerable and results in durable responses [abstract 0559]. Haematologica 95 (Suppl. 2), 230 (2010).
  112. Viardot, A. et al. Treatment of patients with non-Hodgkin lymphoma (NHL) with CD19/CD3 bispecific antibody blinatumomab (MT103): double-step dose increase to continuous infusion of 60 μg/m2/d is tolerable and highly effective [abstract]. Blood 116, a2880 (2010).
  113. Holliger, P., Prospero, T. & Winter, G. “Diabodies”: small bivalent and bispecific antibody fragments. Proc. Natl Acad. Sci. USA 90, 6444–6448 (1993). CAS | PubMed | Article
  114. Moore, P. A. et al. Application of dual affinity retargeting molecules to achieve optimal redirected T-cell killing of B-cell lymphoma. Blood 117, 4542–4551 (2011). CAS | PubMed | Article
  115. Kipriyanov, S. M. et al. Bispecific tandem diabody for tumor therapy with improved antigen binding and pharmacokinetics. J. Mol. Biol. 293, 41–56 (1999). CAS | ISI | PubMed | Article
  116. Brinkmann, U., Reiter, Y., Jung, S. H., Lee, B. & Pastan, I. A recombinant immunotoxin containing a disulfide-stabilized Fv fragment. Proc. Natl Acad. Sci. USA 90, 7538–7542 (1993). CAS | PubMed | Article
  117. Johnson, S. et al. Effector cell recruitment with novel Fv-based dual-affinity re-targeting protein leads to potent tumor cytolysis and in vivo B-cell depletion. J. Mol. Biol. 399, 436–449 (2010). CAS | PubMed | Article
  118. Rothe, A. et al. A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma. Blood 125, 4024–4031 (2015). CAS | PubMed | Article
  119. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012). CAS | ISI | PubMed | Article
  120. Dong, H. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8, 793–800 (2002). CAS | ISI | PubMed | Article
  121. Curiel, T. J. et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat. Med. 9, 562–567 (2003). CAS | ISI | PubMed | Article
  122. Ruiz-Cabello, F. et al. Phenotypic expression of histocompatibility antigens in human primary tumours and metastases. Clin. Exp. Metastasis 7, 213–226 (1989). CAS | PubMed | Article
  123. Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996). CAS | ISI | PubMed | Article
  124. Linsley, P. S. et al. Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. Immunity 4, 535–543 (1996). CAS | ISI | PubMed | Article
  125. Linsley, P. S. et al. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1, 793–801 (1994). CAS | ISI | PubMed | Article
  126. Lenschow, D. J. et al. CD28/B7 regulation of TH1 and TH2 subsets in the development of autoimmune diabetes. Immunity 5, 285–293 (1996). CAS | ISI | PubMed | Article
  127. Parry, R. V. et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell Biol. 25, 9543–9553 (2005). CAS | ISI | PubMed | Article
  128. Latchman, Y. E. et al. PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells. Proc. Natl Acad. Sci. USA 101, 10691–10696 (2004). CAS | PubMed | Article
  129. Nishimura, H., Nose, M., Hiai, H., Minato, N. & Honjo, T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11, 141–151 (1999). CAS | ISI | PubMed | Article
  130. Gotsman, I. et al. Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice. J. Clin. Invest. 117, 2974–2982 (2007). CAS | ISI | PubMed | Article
  131. Waterhouse, P. et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270, 985–988 (1995). CAS | ISI | PubMed | Article
  132. Tivol, E. A. et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3, 541–547 (1995). CAS | ISI | PubMed | Article
  133. Green, M. R. 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 116, 3268–3277 (2010). CAS | ISI | PubMed | Article
  134. Chen, B. J. et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin. Cancer Res. 19, 3462–3473 (2013). CAS | PubMed | Article
  135. Andorsky, D. 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. 17, 4232–4244 (2011).CAS | ISI | PubMed | Article
  136. Naidoo, J., Page, D. B. & Wolchok, J. D. Immune checkpoint blockade. Hematol. Oncol. Clin. North Am. 28, 585–600 (2014). ISI | PubMed | Article
  137. Green, M. R. 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. 18, 1611–1618 (2012). CAS | PubMed | Article
  138. Spranger, S. et al. Up-regulation of PD-L1, IDO, and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci. Transl. Med. 5, 200ra116 (2013). CAS | PubMed | Article
  139. Taube, J. M. et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin. Cancer Res. 20, 5064–5074 (2014). CAS | ISI | PubMed | Article
  140. Steidl, C. et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 471, 377–381 (2011). CAS | ISI | PubMed | Article
  141. Joos, S. et al. Genomic imbalances including amplification of the tyrosine kinase gene JAK2 in CD30+ Hodgkin cells. Cancer Res. 60, 549–552 (2000). CAS | ISI | PubMed
  142. Berger, R. 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. 14, 3044–3051 (2008). CAS | ISI | PubMed | Article
  143. Armand, P. 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. 31, 4199–4206 (2013). CAS | ISI | PubMed | Article
  144. Westin, J. R. 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. 15, 69–77 (2014). CAS | ISI | PubMed | Article
  145. Timmerman, J. et al. Nivolumab in patients with relapsed or refractory lymphoid malignancies and classical Hodgkin lymphoma: updated results of a phase I study (CA209-039) [abstract]. Hematol. Oncol. 33, a010 (2015).
  146. Garcia-Manero, G. et al. A multicohort trial of the safety and efficacy of the PD-1 inhibitor MK-3475 in patients with hematologic malignancies [abstract]. J. Clin. Oncol. 32 (5s Suppl.), TPS3116 (2014).
  147. US National Library of Medicine. ClinicalTrials.gov [online], (2015).
  148. Ansell, S. M. et al. PD-1 Blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N. Engl. J. Med. 372, 311–319 (2015). CAS | ISI | PubMed | Article
  149. Armand, P. et al. Nivolumab in patients with relapsed or refractory Hodgkin lymphoma—preliminary safety, efficacy and biomarker results of a phase I study [abstract]. Blood 124, a289 (2014).
  150. Moskowitz, C. H. et al. 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) [abstract]. Blood 124, a290 (2014).
  151. Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012). CAS | ISI | PubMed | Article
  152. US National Library of Medicine. ClinicalTrials.gov [online], (2015).
  153. US National Library of Medicine. ClinicalTrials.gov [online], (2015).
  154. Ansell, S. M. 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. 15, 6446–6453 (2009). CAS | ISI | PubMed | Article
  155. Weber, J. S. Practical management of immune-related adverse events from immune checkpoint protein antibodies for the oncologist. Am. Soc. Clin. Oncol. Educ. Book 2012, 174–177 (2012).
  156. Weber, J. S., Yang, J. C., Atkins, M. B. & Disis, M. L. Toxicities of immunotherapy for the practitioner. J. Clin. Oncol. 33, 2092–2099 (2015). CAS | PubMed | Article
  157. Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015). CAS | PubMed | Article
  158. Bristol-Myers Squibb Yervoy (ipilimumab): Immune-mediated adverse reaction management guide [online].
  159. Lesokhin, A. M. et al. Preliminary results of a phase I study of nivolumab (BMS-936558) in patients with relapsed or refractory lymphoid malignancies [abstract]. Blood 124, a291 (2014).
  160. US National Library of Medicine. ClinicalTrials.gov [online], (2015).
  161. US National Library of Medicine. ClinicalTrials.gov [online], (2015).
  162. US National Library of Medicine. ClinicalTrials.gov [online], (2015).
  163. US National Library of Medicine. ClinicalTrials.gov [online], (2015).
  164. Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015). PubMed | Article
  165. Carbognin, L. et al. Differential activity of nivolumab, pembrolizumab and MPDL3280A according to the tumor expression of programmed death-ligand-1 (PD-L1): sensitivity analysis of trials in melanoma, lung and genitourinary cancers. PLoS ONE 10, e0130142 (2015). PubMed | Article
  166. Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014). CAS | ISI | PubMed | Article
  167. Rizvi, N. A. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015). CAS | ISI | PubMed | Article
  168. Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014). CAS | ISI | PubMed | Article
  169. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013). CAS | ISI | PubMed | Article
  170. Reichel, J. et al. Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed–Sternberg cells. Blood 125, 1061–1072 (2015). CAS | PubMed | Article
  171. Lin, J. H. et al. Epstein-Barr virus LMP2A suppresses MHC class II expression by regulating the B-cell transcription factors E47 and PU.1. Blood 125, 2228–2238 (2015). CAS | PubMed | Article
  172. Bashey, A. et al. CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood 113, 1581–1588 (2009). CAS