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Bispecific Antibodies for Non-Hodgkin Lymphoma Treatment

  • Lymphoma (JL Muñoz, Section Editor).
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion Statement

While there have been numerous advances in the field of non-Hodgkin lymphoma (NHL) over the last decade, relapsed and/or refractory (R/R) NHL remains a challenge and an area with unmet needs. T-cell redirecting immunotherapeutic approaches including chimeric antigen receptor (CAR) T-cells and bispecific antibodies (BsAbs) have the potential to revolutionize NHL therapy. BsAbs target CD3 on T-cells and CD19 or CD20 on malignant B-cells and have shown promises as a novel immunotherapy for NHL. The development of CD19 × CD3 BsAbs such as blinatumomab was met with significant challenges due to dose-limiting neurologic side effects. However, several CD20 × CD3 BsAbs including odronextamab, mosunetuzumab, glofitamab, and epcoritamab emerged recently. They have favorable toxicity profiles, with reduced cytokine release syndrome and neurotoxicity. In addition, all these BsAbs have demonstrated very promising efficacy in R/R NHL. With expansion and registrational studies actively ongoing, approvals of these agents for R/R NHL are anticipated in the near future. Some important questions pertinent to future clinical development of BsAbs include when and how to best utilize BsAbs in the management of R/R NHL, whether there is a role of BsAbs in treatment-naïve NHL, and how to combine BsAbs with other therapies. For example, whether BsAbs can be combined with cytotoxic chemotherapy effectively remains to be seen. A plethora of clinical studies will be needed to help address these questions, some of which are already ongoing. In addition, how do BsAbs compare to CAR T-cell therapy and how to choose and sequence between BsAbs and CAR T-cell therapy need to be addressed. While many of these critical questions remain to be answered in clinical studies, we believe the future of BsAbs in the NHL is very bright.

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References and Recommended Reading

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

  1. Miller RA, Maloney DG, Warnke R, Levy R. Treatment of B-cell lymphoma with monoclonal anti-idiotype antibody. The New England journal of medicine. 1982;306(9):517–22.

    Article  CAS  Google Scholar 

  2. Johnson S, Burke S, Huang L, Gorlatov S, Li H, Wang W, 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. Journal of molecular biology. 2010;399(3):436–49.

    Article  CAS  Google Scholar 

  3. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young Adults with B-cell lymphoblastic leukemia. The New England journal of medicine. 2018;378(5):439–48.

    Article  CAS  Google Scholar 

  4. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. The New England journal of medicine. 2017;377(26):2531–44.

    Article  CAS  Google Scholar 

  5. •• Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. The New England journal of medicine. 2019;380(1):45–56 This pivotal JULIET trial led to the approval of Tisa-cel CAR-T product for R/R NHL.

    Article  CAS  Google Scholar 

  6. •• Abramson JS, Palomba ML, Gordon LI, Lunning MA, Wang M, Arnason J, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet (London, England). 2020;396(10254):839–52 This was the first CAR-T trial to study CAR T-cells in patients with mantle cell lymphoma, and based on excellent ORR and CR rates was approved in 2020.

    Article  Google Scholar 

  7. Wang M, Munoz J, Goy A, Locke FL, Jacobson CA, Hill BT, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. The New England journal of medicine. 2020;382(14):1331–42.

    Article  CAS  Google Scholar 

  8. Jacobson C, Chavez JC, Sehgal AR, William BM, Munoz J, Salles G, et al. Primary analysis of Zuma-5: a phase 2 study of axicabtagene ciloleucel (Axi-Cel) in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Blood. 2020;136(Supplement 1):40–1.

    Google Scholar 

  9. Löffler A, Kufer P, Lutterbüse R, Zettl F, Daniel PT, Schwenkenbecher JM, et al. A recombinant bispecific single-chain antibody, CD19 x CD3, induces rapid and high lymphoma-directed cytotoxicity by unstimulated T lymphocytes. Blood. 2000;95(6):2098–103.

    Article  Google Scholar 

  10. Offner S, Hofmeister R, Romaniuk A, Kufer P, Baeuerle PA. Induction of regular cytolytic T cell synapses by bispecific single-chain antibody constructs on MHC class I-negative tumor cells. Molecular immunology. 2006;43(6):763–71.

    Article  CAS  Google Scholar 

  11. •• Zhou S, Liu M, Ren F, Meng X, Yu J. The landscape of bispecific T cell engager in cancer treatment. Biomarker Research. 2021;9(1):38 The first BiTE, Blinatumumab that showed promising results for patients with B-ALL, and it is now approved for patients with R/R B-ALL as well as patients who are MRD+ and in the frontline setting with dasatinib.

    Article  Google Scholar 

  12. Goebeler ME, Bargou R. Blinatumomab: a CD19/CD3 bispecific T cell engager (BiTE) with unique anti-tumor efficacy. Leukemia & lymphoma. 2016;57(5):1021–32.

    Article  CAS  Google Scholar 

  13. •• Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. The New England journal of medicine. 2017;376(9):836–47 The first approval of a BiTE in the frontline setting, in combination with dasatinib for untreated Philadelphia chromosome positive B-ALL.

    Article  CAS  Google Scholar 

  14. Topp MS, Kufer P, Gökbuget N, Goebeler M, Klinger M, Neumann 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. Journal of Clinical Oncology. 2011;29(18):2493–8.

    Article  CAS  Google Scholar 

  15. Foà R, Bassan R, Vitale A, Elia L, Piciocchi A, Puzzolo MC, et al. Dasatinib-blinatumomab for Ph-positive acute lymphoblastic leukemia in adults. The New England journal of medicine. 2020;383(17):1613–23.

    Article  Google Scholar 

  16. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, et al. Cytokine release syndrome. Journal for immunotherapy of cancer. 2018;6(1):56.

    Article  Google Scholar 

  17. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016;127(26):3321–30.

    Article  CAS  Google Scholar 

  18. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188–95.

    Article  CAS  Google Scholar 

  19. Schuster SJ, Bartlett NL, Assouline S, Yoon S-S, Bosch F, Sehn LH, et al. Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor T-cell (CAR-T) therapies, and is active in treatment through multiple lines. Blood. 2019;134(Supplement_1):6.

    Article  Google Scholar 

  20. Goebeler ME, Knop S, Viardot A, Kufer P, Topp MS, Einsele H, et al. Bispecific T-Cell Engager (BiTE) Antibody construct blinatumomab for the treatment of patients with relapsed/refractory non-Hodgkin lymphoma: final results from a phase I study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016;34(10):1104–11.

    Article  CAS  Google Scholar 

  21. Viardot A, Goebeler ME, Hess G, Neumann S, Pfreundschuh M, Adrian N, et al. Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. Blood. 2016;127(11):1410–6.

    Article  CAS  Google Scholar 

  22. Coyle L, Morley NJ, Rambaldi A, Mason KD, Verhoef G, Furness CL, et al. Open-label, phase 2 study of blinatumomab as second salvage therapy in adults with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Leukemia & lymphoma. 2020;61(9):2103–12.

    Article  CAS  Google Scholar 

  23. Katz DA, Chu MP, David KA, Thieblemont C, Morley NJ, Khan SS, et al. Open-label, phase 2 study of blinatumomab after first-line rituximab-chemotherapy in adults with newly diagnosed, high-risk diffuse large B-cell lymphoma. Blood. 2019;134(Supplement_1):4077.

    Article  Google Scholar 

  24. Popplewell L, Verhoef G, Kuruvilla J, Tuglus C, Kischel R, Stieglmaier J, et al. A first-in-human study of a half-life extended cd19-targeting bite in relapsed/refractory diffuse large b cell lymphoma, mantle cell lymphoma or follicular lymphoma. Hematological Oncology. 2019;37(S2):566–7.

    Article  Google Scholar 

  25. Reusch U, Duell J, Ellwanger K, Herbrecht C, Knackmuss SH, Fucek I, et al. A tetravalent bispecific TandAb (CD19/CD3), AFM11, efficiently recruits T cells for the potent lysis of CD19(+) tumor cells. mAbs. 2015;7(3):584–604.

    Article  CAS  Google Scholar 

  26. Moore PA, Zhang W, Rainey GJ, Burke S, Li H, Huang L, et al. Application of dual affinity retargeting molecules to achieve optimal redirected T-cell killing of B-cell lymphoma. Blood. 2011;117(17):4542–51.

    Article  CAS  Google Scholar 

  27. Rader C. DARTs take aim at BiTEs. Blood. 2011;117(17):4403–4.

    Article  CAS  Google Scholar 

  28. •• Bannerji R, Allan JN, Arnason JE, Brown JR, Advani R, Ansell SM, et al. Odronextamab (REGN1979), a human CD20 x CD3 bispecific antibody, induces durable, complete responses in patients with highly refractory B-cell non-Hodgkin lymphoma, including patients refractory to CAR T therapy. Blood. 2020;136(Supplement 1):42–3 Odronextamab is a promising bispecific antibody, updated single agent efficacy and safety data in patients with R/R NHL was presented at ASH 2020.

    Article  Google Scholar 

  29. •• Matasar MJ, Cheah CY, Yoon DH, Assouline SE, Bartlett NL, Ku M, et al. Subcutaneous mosunetuzumab in relapsed or refractory B-cell lymphoma: promising safety and encouraging efficacy in dose escalation cohorts. Blood. 2020;136(Supplement 1):45–6 Mosunetuzumab is a bispecific antibody that is administered subcutaneously, preliminary single agent efficacy and safety data for patients with R/R NHL was presented at ASH 2020.

    Article  Google Scholar 

  30. Assouline SE, Kim WS, Sehn LH, Schuster SJ, Cheah CY, Nastoupil LJ, et al. Mosunetuzumab shows promising efficacy in patients with multiply relapsed follicular lymphoma: updated clinical experience from a phase I dose-escalation trial. Blood. 2020;136(Supplement 1):42–4.

    Article  Google Scholar 

  31. •• Olszewski AJ, Avigdor A, Babu S, Levi I, Abadi U, Holmes H, et al. Single-agent mosunetuzumab is a promising safe and efficacious chemotherapy-free regimen for elderly/unfit patients with previously untreated diffuse large B-cell lymphoma. Blood. 2020;136(Supplement 1):43–5 Mosunetuzumab has promising single agent efficacy results for elderly or unfit patients as first line treatment instead of standard chemoimmunotherapy.

    Article  Google Scholar 

  32. Phillips TJ, Olszewski AJ, Munoz J, Kim TM, Yoon DH, Greil R, et al. Mosunetuzumab, a novel CD20/CD3 bispecific antibody, in combination with CHOP confers high response rates in patients with diffuse large B-cell lymphoma. Blood. 2020;136(Supplement 1):37–8.

    Article  Google Scholar 

  33. Hutchings M, Carlo-Stella C, Bachy E, Offner FC, Morschhauser F, Crump M, et al. Glofitamab step-up dosing induces high response rates in patients with hard-to-treat refractory or relapsed non-Hodgkin lymphoma. Blood. 2020;136(Supplement 1):46–8.

    Article  Google Scholar 

  34. Hutchings M, Morschhauser F, Iacoboni G, Carlo-Stella C, Offner FC, Sureda A et al. Glofitamab, a novel, bivalent CD20-targeting T-cell-engaging bispecific antibody, induces durable complete remissions in relapsed or refractory B-cell lymphoma: a phase I trial. J Clin Oncol Off J Am Soc Clin Oncol. 2021:Jco2003175. The results of the phase I study of the bispecific antibody Glofitamab in patients with R/R NHL was published in JCO. In a heavily pre-treated population, there were excellent ORR and CR rates.

  35. Hutchings M, Mous R, Clausen MR, Johnson P, Linton KM, Chamuleau MED, et al. Subcutaneous epcoritamab induces complete responses with an encouraging safety profile across relapsed/refractory B-cell non-Hodgkin lymphoma subtypes, including patients with prior CAR-T therapy: Updated Dose Escalation Data. Blood. 2020;136(Supplement 1):45–6.

    Article  Google Scholar 

  36. Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. The Lancet Oncology. 2019;20(1):31–42.

    Article  CAS  Google Scholar 

  37. Whittington MD, McQueen RB, Campbell JD. Valuing chimeric antigen receptor T-cell therapy: current evidence, uncertainties, and payment implications. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020;38(4):359–66.

    Article  Google Scholar 

  38. Telio D, Fernandes K, Ma C, Tsang R, Keating A, Crump M, et al. Salvage chemotherapy and autologous stem cell transplant in primary refractory diffuse large B-cell lymphoma: outcomes and prognostic factors. Leukemia & lymphoma. 2012;53(5):836–41.

    Article  CAS  Google Scholar 

  39. Jung D, Jain P, Yao Y, Wang M. Advances in the assessment of minimal residual disease in mantle cell lymphoma. Journal of hematology & oncology. 2020;13(1):127.

    Article  Google Scholar 

  40. Diamond B, Kumar A. Mantle cell lymphoma: current and emerging treatment strategies and unanswered questions. Hematology/oncology clinics of North America. 2019;33(4):613–26.

    Article  Google Scholar 

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Correspondence to Yucai Wang MD, PhD.

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Conflict of Interest

Allison M. Bock declares that she has no conflict of interest. Grzegorz S. Nowakowski has received research funding (paid to his institution) from Celgene/Bristol-Myers Squibb, Roche, Genentech, and NanoString Technologies, and has received compensation for service as a consultant from MorphoSys, Celgene/Bristol-Myers Squibb, Roche, Genentech, Kite Pharma, Ryvu Therapeutics, Selvita, Curis, Karyopharm Therapeutics, Bantam Pharmaceutical, Daiichi Sankyo, Zai Lab, Incyte Corporation, TG Therapeutics, and Blueprint Medicines. Yucai Wang has received research funding (paid to his institution) from Incyte Corporation, InnoCare, LOXO Oncology, Novartis, and Genentech; and has served on advisory boards for Incyte Corporation, LOXO Oncology, Eli Lilly, and TG Therapeutics. All compensation was paid directly to his institution.

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Bock, A.M., Nowakowski, G.S. & Wang, Y. Bispecific Antibodies for Non-Hodgkin Lymphoma Treatment. Curr. Treat. Options in Oncol. 23, 155–170 (2022). https://doi.org/10.1007/s11864-021-00925-1

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