“A.B.C.” of Immunotherapy in Hematological Malignancies…Promise and Perils

 

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Abstract

The treatment landscape of hematological malignancies has been evolving at an extremely fast pace. Hematological malignancies are diverse and distinct from solid tumors. These constitute challenges, which are also unique opportunities for immunotherapy. The five categories of immunotherapies that have found success in the management of hematological malignancies are allogeneic hematopoietic stem cell transplant, monoclonal antibodies and innovative designs, immune checkpoint inhibitors, chimeric antigen receptor (CAR) T cells, and B cell targeting small immunomodulatory molecules. Allogeneic stem cell transplant rightly called our bluntest weapon is the oldest form of successful immunotherapy. Alternate donor transplants and improvement in supportive care have improved the scope of this immunotherapy option. Among monoclonal antibodies, rituximab forms the prototype on which over a dozen other antibodies have been developed. The bispecific T-cell engager (BiTE) blinatumomab engages cytotoxic CD3 T cells with CD19 acute lymphoblastic leukemia (ALL) cells, which is an effective treatment method for relapsed refractory ALL. Immune checkpoint inhibitors have established their role in hematological malignancies with high PD-L1 expression, including relapsed refractory Hodgkin's lymphoma and primary mediastinal B cell lymphoma (BCL). Small immunomodulatory drugs targeting the B cell receptor downstream signaling through BTK inhibitors, SYK inhibitors, PI3K inhibitors (idelalisib), and BCL-2 inhibitors (venetoclax), and immunomodulatory imide drugs (lenalidomide) have also emerged as exciting therapeutic avenues in immunotherapy. CAR T cells are one of the most exciting and promising forms of adoptive immunotherapy. CAR T cells are rightly called living drugs or serial killers to keep patients alive. CAR T cells are genetically engineered, autologous T cells that combine the cytotoxicity of T cells with the antigen-binding specificity of CARs. CARs are antigen-specific but major histocompatibility complex/human leukocyte antigen-independent. There are five approved CAR T cell products for the management of relapsed refractory leukemias, lymphoma, and multiple myeloma. The past and present of immunotherapy have been really exciting and the future looks incredibly promising. The challenges include widening the availability and affordability beyond specialized centers, identification of potentially predictive biomarkers of response, and experience in the management of complications of these novel agents. The combinational approach of multiple immunotherapies might be the way forward to complement the treatment strategies to harness the immune system and to improve survival with good quality of life.

Publication History

Article published online:
28 November 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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• References

• 1 Horowitz MM, Gale RP, Sondel PM. et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990; 75 (03) 555-562
  CrossrefPubMedGoogle Scholar
• 2 Weiden PL, Flournoy N, Thomas ED. et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med 1979; 300 (19) 1068-1073
  CrossrefPubMedGoogle Scholar
• 3 Duval M, Klein JP, He W. et al. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol 2010; 28 (23) 3730-3738
  CrossrefPubMedGoogle Scholar
• 4 Lieskovsky YE, Donaldson SS, Torres MA. et al. High-dose therapy and autologous hematopoietic stem-cell transplantation for recurrent or refractory pediatric Hodgkin's disease: results and prognostic indices. J Clin Oncol 2004; 22 (22) 4532-4540
  CrossrefPubMedGoogle Scholar
• 5 Collins Jr RH, Shpilberg O, Drobyski WR. et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 1997; 15 (02) 433-444
  CrossrefPubMedGoogle Scholar
• 6 Carella AM, Giralt S, Slavin S. Low intensity regimens with allogeneic hematopoietic stem cell transplantation as treatment of hematologic neoplasia. Haematologica 2000; 85 (03) 304-313
  PubMedGoogle Scholar
• 7 Kanakry CG, Fuchs EJ, Luznik L. Modern approaches to HLA-haploidentical blood or marrow transplantation. Nat Rev Clin Oncol 2016; 13 (01) 10-24
  CrossrefPubMedGoogle Scholar
• 8 Ciurea SO, Zhang MJ, Bacigalupo AA. et al. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood 2015; 126 (08) 1033-1040
  CrossrefPubMedGoogle Scholar
• 9 Scott AM, Allison JP, Wolchok JD. Monoclonal antibodies in cancer therapy. Cancer Immun 2012; 12: 14
  PubMedGoogle Scholar
• 10 Wu J, Fu J, Zhang M, Liu D. Blinatumomab: a bispecific T cell engager (BiTE) antibody against CD19/CD3 for refractory acute lymphoid leukemia. J Hematol Oncol 2015; 8: 104
  CrossrefPubMedGoogle Scholar
• 11 Fan D, Li W, Yang Y. et al. Redirection of CD4+ and CD8+ T lymphocytes via an anti-CD3 × anti-CD19 bi-specific antibody combined with cytosine arabinoside and the efficient lysis of patient-derived B-ALL cells. J Hematol Oncol 2015; 8: 108
  CrossrefPubMedGoogle Scholar
• 12 Topp MS, Gökbuget N, Stein AS. 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 2015; 16 (01) 57-66
  CrossrefPubMedGoogle Scholar
• 13 Scott DW, Gascoyne RD. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer 2014; 14 (08) 517-534
  CrossrefPubMedGoogle Scholar
• 14 Kline J, Godfrey J, Ansell SM. The immune landscape and response to immune checkpoint blockade therapy in lymphoma. Blood 2020; 135 (08) 523-533
  CrossrefPubMedGoogle Scholar
• 15 Xu-Monette ZY, Zhou J, Young KH. PD-1 expression and clinical PD-1 blockade in B-cell lymphomas. Blood 2018; 131 (01) 68-83
  CrossrefPubMedGoogle Scholar
• 16 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 (06) 1611-1618
  CrossrefPubMedGoogle Scholar
• 17 Roemer MG, Advani RH, Ligon AH. et al. PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J Clin Oncol 2016; 34 (23) 2690-2697
  CrossrefPubMedGoogle Scholar
• 18 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 (04) 311-319
  CrossrefPubMedGoogle Scholar
• 19 Armand P, Shipp MA, Ribrag V. et al. Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol 2016; 34 (31) 3733-3739
  CrossrefPubMedGoogle Scholar
• 20 Armand P, Engert A, Younes A. et al. Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 trial. J Clin Oncol 2018; 36 (14) 1428-1439
  CrossrefPubMedGoogle Scholar
• 21 Ramchandren R, Domingo-Domènech E, Rueda A. et al. Nivolumab for newly diagnosed advanced-stage classic Hodgkin lymphoma: safety and efficacy in the phase II CheckMate 205 study. J Clin Oncol 2019; 37 (23) 1997-2007
  CrossrefPubMedGoogle Scholar
• 22 Younes A, Santoro A, Shipp M. et al. Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 2016; 17 (09) 1283-1294
  CrossrefPubMedGoogle Scholar
• 23 Chen R, Zinzani PL, Fanale MA. et al; KEYNOTE-087. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol 2017; 35 (19) 2125-2132
  CrossrefPubMedGoogle Scholar
• 24 Maus MV, Grupp SA, Porter DL, June CH. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 2014; 123 (17) 2625-2635
  CrossrefPubMedGoogle Scholar
• 25 Coiffier B, Haioun C, Ketterer N. et al. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood 1998; 92 (06) 1927-1932
  PubMedGoogle Scholar
• 26 Coiffier B, Lepage E, Briere J. et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346 (04) 235-242
  CrossrefPubMedGoogle Scholar
• 27 Casak SJ, Lemery SJ, Shen YL. et al. U.S. Food and Drug Administration approval: rituximab in combination with fludarabine and cyclophosphamide for the treatment of patients with chronic lymphocytic leukemia. Oncologist 2011; 16 (01) 97-104
  CrossrefPubMedGoogle Scholar
• 28 Salles G, Seymour JF, Offner F. et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011; 377 (9759): 42-51
  CrossrefPubMedGoogle Scholar
• 29 Lemery SJ, Zhang J, Rothmann MD. et al. U.S. Food and Drug Administration approval: ofatumumab for the treatment of patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab. Clin Cancer Res 2010; 16 (17) 4331-4338
  CrossrefPubMedGoogle Scholar
• 30 Lee HZ, Miller BW, Kwitkowski VE. et al. U.S. Food and Drug Administration approval: obinutuzumab in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia. Clin Cancer Res 2014; 20 (15) 3902-3907
  CrossrefPubMedGoogle Scholar
• 31 Sehn LH, Chua N, Mayer J. et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol 2016; 17 (08) 1081-1093
  CrossrefPubMedGoogle Scholar
• 32 Salles G, Duell J, González Barca E. et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol 2020; 21 (07) 978-988
  CrossrefPubMedGoogle Scholar
• 33 Hillmen P, Skotnicki AB, Robak T. et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol 2007; 25 (35) 5616-5623
  CrossrefPubMedGoogle Scholar
• 34 Keating MJ, Flinn I, Jain V. et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 2002; 99 (10) 3554-3561
  CrossrefPubMedGoogle Scholar
• 35 Kasamon YL, Chen H, de Claro RA. et al. FDA approval summary: mogamulizumab-kpkc for mycosis fungoides and Sezary syndrome. Clin Cancer Res 2019; 25 (24) 7275-7280
  CrossrefPubMedGoogle Scholar
• 36 Bhatnagar V, Gormley NJ, Luo L. et al. FDA approval summary: daratumumab for treatment of multiple myeloma after one prior therapy. Oncologist 2017; 22 (11) 1347-1353
  CrossrefPubMedGoogle Scholar
• 37 Attal M, Richardson PG, Rajkumar SV. et al; ICARIA-MM study group. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet 2019; 394 (10214): 2096-2107
  CrossrefPubMedGoogle Scholar
• 38 Lonial S, Dimopoulos M, Palumbo A. et al; ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med 2015; 373 (07) 621-631
  CrossrefPubMedGoogle Scholar
• 39 Horwitz S, O'Connor OA, Pro B. et al; ECHELON-2 Study Group. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet 2019; 393 (10168): 229-240
  CrossrefPubMedGoogle Scholar
• 40 Straus DJ, Długosz-Danecka M, Alekseev S. et al. Brentuximab vedotin with chemotherapy for stage III/IV classical Hodgkin lymphoma: 3-year update of the ECHELON-1 study. Blood 2020; 135 (10) 735-742
  CrossrefPubMedGoogle Scholar
• 41 Kreitman RJ, Dearden C, Zinzani PL. et al. Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia. Leukemia 2018; 32 (08) 1768-1777
  CrossrefPubMedGoogle Scholar
• 42 Castaigne S, Pautas C, Terré C. et al; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet 2012; 379 (9825): 1508-1516
  CrossrefPubMedGoogle Scholar
• 43 FDA approves gemtuzumab ozogamicin for CD33-positive AML in pediatric patients; 2020. https://www.fda.gov/drugs/development-approval-process-drugs/drug-approvals-and-databases
• 44 Sehn LH, Herrera AF, Flowers CR. et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 2020; 38 (02) 155-165
  CrossrefPubMedGoogle Scholar
• 45 Maude SL, Frey N, Shaw PA. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014; 371 (16) 1507-1517
  CrossrefPubMedGoogle Scholar
• 46 Neelapu SS, Locke FL, Bartlett NL. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 2017; 377 (26) 2531-2544
  CrossrefPubMedGoogle Scholar
• 47 Schuster SJ, Bishop MR, Tam CS. et al; JULIET Investigators. JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med 2019; 380 (01) 45-56
  CrossrefPubMedGoogle Scholar
• 48 Wang M, Munoz J, Goy A. et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2020; 382 (14) 1331-1342
  CrossrefPubMedGoogle Scholar
• 49 Abramson JS, Palomba ML, Gordon LI. et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet 2020; 396 (10254): 839-852
  CrossrefPubMedGoogle Scholar
• 50 Jacobson C, Chavez J, Sehgal A. 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: 40-41
  CrossrefGoogle Scholar