Skip to main content

Advertisement

SpringerLink
Log in

Current combinatorial CAR T cell strategies with Bruton tyrosine kinase inhibitors and immune checkpoint inhibitors

  • Review Article
  • Published:
Bone Marrow Transplantation Submit manuscript

Abstract

CD19-targeted chimeric antigen receptor (CAR) T cell therapy has shown high efficacy in patients with refractory B-cell malignancies such as non-Hodgkin lymphoma and acute lymphoblastic leukemia. Despite promising results, responses are not durable in most patients. In addition, patients receiving CD19 CAR T cell therapy are at risk of developing severe, potentially life-threatening, adverse events including cytokine release syndrome and immune effector-cell associated neurotoxicity syndrome. Many combinatorial approaches are currently being investigated to improve CAR T cell in vivo function, antitumor effects, and mitigate toxicities. In this review, we discuss the use of ibrutinib and immune checkpoint inhibitors in combination with CAR T cell therapy in patients with lymphoid B-cell malignancies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1: Key targetable avenues to improve outcomes after CAR T-cell therapy.

Similar content being viewed by others

References

  1. Gauthier J, Yakoub-Agha I. Chimeric antigen-receptor T-cell therapy for hematological malignancies and solid tumors: clinical data to date, current limitations and perspectives. Curr Res Transl Med. 2017;65:93–102.

    Article  PubMed  CAS  Google Scholar 

  2. 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. N Engl J Med. 2018;378:439–48.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. 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. Lancet Oncol. 2019;20:31–42.

    Article  PubMed  CAS  Google Scholar 

  4. Turtle CJ, Hanafi LA, Berger C, Hudecek M, Pender B, Robinson E, et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med. 2016;8:355ra116.

    Article  PubMed  PubMed Central  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. N Engl J Med. 2018;380:45–56.

    Article  PubMed  Google Scholar 

  6. Turtle CJ, Hay KA, Hanafi L-A, Li D, Cherian S, Chen X, et al. Durable Molecular Remissions in Chronic Lymphocytic Leukemia Treated With CD19-Specific Chimeric Antigen Receptor–Modified T Cells After Failure of Ibrutinib. J Clin Oncol. 2017;35:3010–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Gauthier J, Hirayama AV, Purushe J, Hay KA, Lymp J, Li DH, et al. Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL after ibrutinib failure. Blood. 2020;135:1650–60.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Brudno JN, Maric I, Hartman SD, Rose JJ, Wang M, Lam N, et al. T Cells Genetically Modified to Express an Anti–B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma. J Clin Oncol. 2018;36:2267–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Raje N, Berdeja J, Lin Y, Siegel D, Jagannath S, Madduri D, et al. Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2019;380:1726–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Cowan AJ, Pont M, Sather BD, Turtle CJ, Till BG, Nagengast AM, et al. Efficacy and Safety of Fully Human Bcma CAR T Cells in Combination with a Gamma Secretase Inhibitor to Increase Bcma Surface Expression in Patients with Relapsed or Refractory Multiple Myeloma. Blood. 2019;134:204. (Supplement_1).

    Article  Google Scholar 

  11. Green DJ, Pont M, Cowan AJ, Cole GO, Sather BD, Nagengast AM, et al. Response to Bcma CAR-T Cells Correlates with Pretreatment Target Antigen Density and Is Improved By Small Molecule Inhibition of Gamma Secretase. Blood. 2019;134:1856. (Supplement_1).

    Article  Google Scholar 

  12. Administration TUSFaD. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-b-cell-all-and-tocilizumab-cytokine-release-syndrome: The U.S. Food and Drug Administration; 2017.

  13. Administration TUSFaD. FDA approves tisagenlecleucel for adults with relapsed or refractory large B-cell lymphoma https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-adults-relapsed-or-refractory-large-b-cell-lymphoma: The U.S. Food and Drug Administration; 2018.

  14. Administration TUSFaD. FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma https://www.fda.gov/news-events/press-announcements/fda-approves-car-t-cell-therapy-treat-adults-certain-types-large-b-cell-lymphoma: The U.S. Food and Drug Administration; 2017.

  15. 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. N Engl J Med. 2017;377:2531–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Administration TUSFaD. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma https://www.fda.gov/drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-mantle-cell-lymphoma: The U.S. Food and Drug Administration; 2020.

  17. 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. N Engl J Med. 2020;382:1331–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Wierda WG, Dorritie KA, Munoz J, Stephens DM, Solomon SR, Gillenwater HH, et al. Transcend CLL 004: Phase 1 Cohort of Lisocabtagene Maraleucel (liso-cel) in Combination with Ibrutinib for Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). Blood. 2020;136:39–40. (Supplement 1).

    Article  Google Scholar 

  19. Munshi NC, Anderson LD Jr, Shah N, Madduri D, Berdeja J, Lonial S, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021;384:705–16.

    Article  PubMed  CAS  Google Scholar 

  20. Fraietta JA, Beckwith KA, Patel PR, Ruella M, Zheng Z, Barrett DM, et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood. 2016;127:1117–27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Fraietta JA, Nobles CL, Sammons MA, Lundh S, Carty SA, Reich TJ, et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature. 2018;558:307–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Sotillo E, Barrett DM, Black KL, Bagashev A, Oldridge D, Wu G, et al. Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy. Cancer Disco. 2015;5:1282–95.

    Article  CAS  Google Scholar 

  23. Fisher J, Abramowski P, Wisidagamage Don ND, Flutter B, Capsomidis A, Cheung GW, et al. Avoidance of On-Target Off-Tumor Activation Using a Co-stimulation-Only Chimeric Antigen Receptor. Mol Ther. 2017;25:1234–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Gardner R, Wu D, Cherian S, Fang M, Hanafi LA, Finney O, et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood. 2016;127:2406–10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Jacoby E, Nguyen SM, Fountaine TJ, Welp K, Gryder B, Qin H, et al. CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. Nat Commun. 2016;7:12320.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Ruella M, Xu J, Barrett DM, Fraietta JA, Reich TJ, Ambrose DE, et al. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat Med. 2018;24:1499–503.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Gauthier J, Turtle CJ. Insights into cytokine release syndrome and neurotoxicity after CD19-specific CAR-T cell therapy. Curr Res Transl Med. 2018;66:50–2.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Sheth VS, Gauthier J. Taming the beast: CRS and ICANS after CAR T-cell therapy for ALL. Bone Marrow Transplant. 2021;56:552–66.

    Article  PubMed  CAS  Google Scholar 

  29. 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. 2020;396:839–52.

    Article  PubMed  Google Scholar 

  30. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365:725–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Geyer MB, Riviere I, Senechal B, Wang X, Wang Y, Purdon TJ, et al. Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL. JCI Insight. 2019;5:e122627. https://doi.org/10.1172/jci.insight.122627.

    Article  Google Scholar 

  32. Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013;122:2539–49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Long M, Beckwith K, Do P, Mundy BL, Gordon A, Lehman AM, et al. Ibrutinib treatment improves T cell number and function in CLL patients. J Clin Investig. 2017;127:3052–64.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Ponader S, Chen S-S, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012;119:1182–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. de Rooij MFM, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor– and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119:2590–4.

    Article  PubMed  CAS  Google Scholar 

  36. Chen SS, Chang BY, Chang S, Tong T, Ham S, Sherry B, et al. BTK inhibition results in impaired CXCR4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia. Leukemia. 2016;30:833–43.

    Article  PubMed  CAS  Google Scholar 

  37. Fan F, Yoo HJ, Stock S, Wang L, Liu Y, Schubert M-L, et al. Ibrutinib for improved chimeric antigen receptor T-cell production for chronic lymphocytic leukemia patients. Int J Cancer. 2021;148:419–28.

    Article  PubMed  CAS  Google Scholar 

  38. Ruella M, Kenderian SS, Shestova O, Klichinsky M, Melenhorst JJ, Wasik MA, et al. Kinase inhibitor ibrutinib to prevent cytokine-release syndrome after anti-CD19 chimeric antigen receptor T cells for B-cell neoplasms. Leukemia. 2017;31:246–8.

    Article  PubMed  CAS  Google Scholar 

  39. Hampel PJ, Chaffee KG, Ding W, Call T, Kenderian S, Muchtar E, et al. Rapid progression of disease following ibrutinib discontinuation in patients with chronic lymphocytic leukemia. J Clin Oncol. 2018;36:7525. (15_suppl).

    Article  Google Scholar 

  40. Gill SI, Vides V, Frey NV, Metzger S, O’Brien M, Hexner E, et al. Prospective Clinical Trial of Anti-CD19 CAR T Cells in Combination with Ibrutinib for the Treatment of Chronic Lymphocytic Leukemia Shows a High Response Rate. Blood. 2018;132:298. (Supplement 1).

    Article  Google Scholar 

  41. Gauthier J, Hirayama AV, Hay KA, Li D, Lymp J, Sheih A, et al. Comparison of Efficacy and Toxicity of CD19-Specific Chimeric Antigen Receptor T-Cells Alone or in Combination with Ibrutinib for Relapsed and/or Refractory CLL. Blood. 2018;132:299. (Supplement 1).

    Article  Google Scholar 

  42. Kittai AS, Bond DA, William B, Saad A, Penza S, Efebera Y, et al. Clinical activity of axicabtagene ciloleucel in adult patients with Richter syndrome. Blood Adv. 2020;4:4648–52.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Mizuno R, Sugiura D, Shimizu K, Maruhashi T, Watada M, Okazaki I-M, et al. PD-1 Primarily Targets TCR Signal in the Inhibition of Functional T Cell Activation. Front Immunol. 2019;10:630. https://doi.org/10.3389/fimmu.2019.00630

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15:486–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Alsaab HO, Sau S, Alzhrani R, Tatiparti K, Bhise K, Kashaw SK, et al. PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. Front Pharmacol. 2017;8:561.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov DS, Jones DR, et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Investig. 2016;126:3130–44.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Deng Q, Han G, Puebla-Osorio N, Ma MCJ, Strati P, Chasen B, et al. Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas. Nat Med. 2020;26:1878–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Jacobson CA, Locke FL, Miklos DB, Herrera AF, Westin JR, Lee J, et al. End of Phase 1 Results from Zuma-6: Axicabtagene Ciloleucel (Axi-Cel) in Combination with Atezolizumab for the Treatment of Patients with Refractory Diffuse Large B Cell Lymphoma. Biol Blood Marrow Transplant. 2019;25:S173. (3, Supplement).

    Article  Google Scholar 

  49. Chong EA, Svoboda J, Dwivedy Nasta S, Landsburg DJ, Winchell N, Napier E, et al. Sequential Anti-CD19 Directed Chimeric Antigen Receptor Modified T-Cell Therapy (CART19) and PD-1 Blockade with Pembrolizumab in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphomas. Blood. 2018;132:4198. (Supplement 1).

    Article  Google Scholar 

  50. Hirayama AV, Gauthier J, Hay KA, Sheih A, Cherian S, Chen X, et al. Efficacy and Toxicity of JCAR014 in Combination with Durvalumab for the Treatment of Patients with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma. Blood. 2018;132:1680. (Supplement 1).

    Article  Google Scholar 

  51. Li AM, Hucks GE, Dinofia AM, Seif AE, Teachey DT, Baniewicz D, et al. Checkpoint Inhibitors Augment CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy in Relapsed B-Cell Acute Lymphoblastic Leukemia. Blood. 2018;132:556. (Supplement 1).

    Article  Google Scholar 

  52. Qin JS, Johnstone TG, Baturevych A, Hause RJ, Ragan SP, Clouser CR, et al. Antitumor Potency of an Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy, Lisocabtagene Maraleucel in Combination With Ibrutinib or Acalabrutinib. J Immunother. 2020;43:107–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Chavez JC, Locke FL, Napier E, Simon C, Lewandowski A, Awasthi R, et al. Ibrutinib before Apheresis May Improve Tisagenlecleucel Manufacturing in Relapsed/Refractory Adult Diffuse Large B-Cell Lymphoma: Initial Results from a Phase 1b Study. Blood. 2020;136:3–4. (Supplement 1).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon

    Razan Mohty

  2. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Jordan Gauthier

  3. Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA

    Jordan Gauthier

Authors
  1. Razan Mohty
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jordan Gauthier
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both R.M. and J.G. designed and wrote the manuscript. J.G. supervised the work.

Corresponding author

Correspondence to Jordan Gauthier.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mohty, R., Gauthier, J. Current combinatorial CAR T cell strategies with Bruton tyrosine kinase inhibitors and immune checkpoint inhibitors. Bone Marrow Transplant 56, 2630–2636 (2021). https://doi.org/10.1038/s41409-021-01420-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-021-01420-9

  • Springer Nature Limited

Search

Navigation