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Anti-CD79b/CD3 bispecific antibody combined with CAR19-T cells for B-cell lymphoma treatment

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Abstract

CD19 CAR-T (chimeric antigen receptor-T) cell immunotherapy achieves a remission rate of approximately 70% in recurrent and refractory lymphoma treatment. However, the loss or reduction of CD19 antigen on the surface of lymphoma cells results in the escape of tumor cells from the immune killing of CD19 CAR-T cells (CAR19-T). Therefore, novel therapeutic strategies are urgently required. In this study, an anti-CD79b/CD3 bispecific antibody (BV28-OKT3) was constructed and combined with CAR19-T cells for B-cell lymphoma treatment. When the CD19 antigen was lost or reduced, BV28-OKT3 redirected CAR19-T cells to CD79b+ CD19– lymphoma cells; therefore, BV28-OKT3 overcomes the escape of CD79b+ CD19– lymphoma cells by the killing action of CAR19-T cells in vitro and in vivo. Furthermore, BV28-OKT3 triggered the antitumor function of CAR– T cells in the infusion product and boosted the antitumor immune response of bystander T cells, markedly improving the cytotoxicity of CAR19-T cells to lymphoma cells in vitro and in vivo. In addition, BV28-OKT3 elicited the cytotoxicity of donor-derived T cells toward lymphoma cells in vitro, which depended on the presence of tumor cells. Therefore, our findings provide a new clinical treatment strategy for recurrent and refractory B-cell lymphoma by combining CD79b/CD3 BsAb with CAR19-T cells.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ANOVA:

One-way analysis of variance

B-ALL:

B-cell acute lymphoblastic leukemia

BCR:

B-cell receptor

BiTE:

Bispecific T-cell engagers

CAR-T:

Chimeric antigen receptor T

CD3-BsAb:

CD3-bispecific antibody

DLBCL:

Diffuse large B-cell lymphoma

NHL:

Non-Hodgkin lymphoma

PBMCs:

Peripheral blood mononuclear cells

scFv:

Single-chain variable fragment

TCR:

T-cell receptor

TILs:

Tumor-infiltrating lymphocytes

References

  1. Wang M, Munoz J, Goy A et al (2020) KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med 382(14):1331–1342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Maude SL, Laetsch TW, Buechner J et al (2018) Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 378(5):439–448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Schuster SJ, Bishop MR, Tam CS et al (2019) Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell Lymphoma. N Engl J Med 380(1):45–56

    Article  CAS  PubMed  Google Scholar 

  4. Neelapu SS, Locke FL, Bartlett NL et al (2017) Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 377(26):2531–2544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Nastoupil LJ, Jain MD, Feng L et al (2020) Standard-of-care axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma: results from the US lymphoma CAR T consortium. J Clin Oncol 38(27):3119–3128

    Article  PubMed  PubMed Central  Google Scholar 

  6. Mueller KT, Maude SL, Porter DL et al (2017) Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia. Blood 130(21):2317–2325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gardner R, Wu D, Cherian S et al (2016) Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood 127(20):2406–2410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wagner J, Wickman E, Derenzo C et al (2020) CAR T cell therapy for solid tumors: bright future or dark reality? Mol Ther 28(11):2320–2339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sotillo E, Barrett DM, Black KL et al (2015) Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov 5(12):1282–1295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Grupp SA, Kalos M, Barrett D et al (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368(16):1509–1518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Shah NN, Johnson BD, Schneider D et al (2020) Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. Nat Med 26(10):1569–1575

    Article  CAS  PubMed  Google Scholar 

  12. Braig F, Brandt A, Goebeler M et al (2017) Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking. Blood 129(1):100–104

    Article  CAS  PubMed  Google Scholar 

  13. Hamieh M, Dobrin A, Cabriolu A et al (2019) CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape. Nature 568(7750):112–116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang LD, Clark MR (2003) B-cell antigen-receptor signalling in lymphocyte development. Immunology 110(4):411–420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. D’arena G, Musto P, Cascavilla N et al (2000) Quantitative flow cytometry for the differential diagnosis of leukemic B-cell chronic lymphoproliferative disorders. Am J Hematol 64(4):275–281

    Article  PubMed  Google Scholar 

  16. Olejniczak SH, Stewart CC, Donohue K et al (2006) A quantitative exploration of surface antigen expression in common B-cell malignancies using flow cytometry. Immunol Invest 35(1):93–114

    Article  CAS  PubMed  Google Scholar 

  17. Choi Y, Diefenbach CS (2020) Polatuzumab Vedotin: a New Target for B Cell Malignancies. Curr Hematol Malig Rep 15(2):125–129

    Article  PubMed  Google Scholar 

  18. Wang J, Li C, He K et al (2022) Characterization of anti-CD79b/CD3 bispecific antibody, a potential therapy for B cell malignancies. Cancer Immunol Immunother 72(2):493–507

    Article  PubMed  Google Scholar 

  19. Wu Z, Cheung NV (2018) T cell engaging bispecific antibody (T-BsAb): from technology to therapeutics. Pharmacol Ther 182:161–175

    Article  CAS  PubMed  Google Scholar 

  20. Frankel SR, Baeuerle PA (2013) Targeting T cells to tumor cells using bispecific antibodies. Curr Opin Chem Biol 17(3):385–392

    Article  CAS  PubMed  Google Scholar 

  21. Goebeler ME, Bargou R (2016) Blinatumomab: a CD19/CD3 bispecific T cell engager (BiTE) with unique anti-tumor efficacy. Leuk Lymphoma 57(5):1021–1032

    Article  CAS  PubMed  Google Scholar 

  22. Goebeler ME, Bargou RC (2020) T cell-engaging therapies - BiTEs and beyond. Nat Rev Clin Oncol 17(7):418–434

    Article  PubMed  Google Scholar 

  23. Khalique H, Baugh R, Dyer A et al (2021) Oncolytic herpesvirus expressing PD-L1 BiTE for cancer therapy: exploiting tumor immune suppression as an opportunity for targeted immunotherapy. J Immunother Cancer 9(4):e001292

    Article  PubMed  PubMed Central  Google Scholar 

  24. Leung WK, Ayanambakkam A, Heslop HE et al (2022) Beyond CD19 CAR-T cells in lymphoma. Curr Opin Immunol 74:46–52

    Article  CAS  PubMed  Google Scholar 

  25. Simoni Y, Becht E, Fehlings M et al (2018) Bystander CD8(+) T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 557(7706):575–579

    Article  CAS  PubMed  Google Scholar 

  26. Meier SL, Satpathy AT, Wells DK (2022) Bystander T cells in cancer immunology and therapy. Nat Cancer 3(2):143–155

    Article  PubMed  Google Scholar 

  27. Kochenderfer JN, Dudley ME, Carpenter RO et al (2013) (2013) Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 122(25):4129–4139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tong C, Zhang Y, Liu Y et al (2020) Optimized tandem CD19/CD20 CAR-engineered T cells in refractory/relapsed B-cell lymphoma. Blood 136(14):1632–1644

    PubMed  PubMed Central  Google Scholar 

  29. Fry TJ, Shah NN, Orentas RJ et al (2018) CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med 24(1):20–28

    Article  CAS  PubMed  Google Scholar 

  30. Kennedy GA, Tey SK, Cobcroft R et al (2002) Incidence and nature of CD20-negative relapses following rituximab therapy in aggressive B-cell non-Hodgkin’s lymphoma: a retrospective review. Br J Haematol 119(2):412–416

    Article  CAS  PubMed  Google Scholar 

  31. Deeks ED (2019) Polatuzumab vedotin: first global approval. Drugs 79(13):1467–1475

    Article  PubMed  PubMed Central  Google Scholar 

  32. Tilly H, Morschhauser F, Sehn LH et al (2021) Polatuzumab Vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med 386(4):351–363

    Article  PubMed  Google Scholar 

  33. Ormhøj M, Scarfò I, Cabral ML et al (2019) Chimeric antigen receptor T Cells targeting CD79b show efficacy in lymphoma with or without cotargeting CD19. Clin Cancer Res 25(23):7046–7057

    Article  PubMed  PubMed Central  Google Scholar 

  34. Choi BD, Yu X, Castano AP et al (2019) CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity. Nat Biotechnol 37(9):1049–1058

    Article  CAS  PubMed  Google Scholar 

  35. Yin Y, Rodriguez JL, Li N et al (2022) Locally secreted BiTEs complement CAR T cells by enhancing killing of antigen heterogeneous solid tumors. Mol Ther 30(7):2537–2553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Spiegel JY, Patel S, Muffly L et al (2021) CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nat Med 27(8):1419–1431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cordoba S, Onuoha S, Thomas S et al (2021) CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial. Nat Med 27(10):1797–1805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bargou R, Leo E, Zugmaier G et al (2008) Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 321(5891):974–977

    Article  CAS  PubMed  Google Scholar 

  39. Trabolsi A, Arumov A, Schatz JH (2019) T cell-activating bispecific antibodies in cancer therapy. J Immunol 203(3):585–592

    Article  CAS  PubMed  Google Scholar 

  40. Liu Z, Zhou Z, Dang Q, Xu H, Lv J, Li H, Han X (2022) Immunosuppression in tumor immune microenvironment and its optimization from CAR-T cell therapy. Theranostics 12(14):6273–6290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Berraondo P, Sanmamed MF, Ochoa MC et al (2019) Cytokines in clinical cancer immunotherapy. Br J Cancer 120(1):6–15

    Article  CAS  PubMed  Google Scholar 

  42. Huarte E, Tirapu I, Arina A et al (2005) Intratumoural administration of dendritic cells: hostile environment and help by gene therapy. Expert Opin Biol Ther 5(1):7–22

    Article  CAS  PubMed  Google Scholar 

  43. Baniel CC, Heinze CM, Hoefges A et al (2020) In situ vaccine plus checkpoint blockade induces memory humoral response. Front Immunol 11:1610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Frank MJ, Reagan PM, Bartlett NL et al (2018) In Situ vaccination with a TLR9 agonist and local low-dose radiation induces systemic responses in untreated indolent lymphoma. Cancer Discov 8(10):1258–1269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Melero I, Castanon E, Alvarez M et al (2021) Intratumoural administration and tumour tissue targeting of cancer immunotherapies. Nat Rev Clin Oncol 18(9):558–576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Ying An for excellent technical support.

Funding

This work is supported by the National Natural Science Foundation of China (NO. 81830004 to A.-B.L.; NO. 82070168 to P.L.; NO. 81800191 to K.Q.; NO. 82070158 to C.-W.D.; NO.32100747 to K.-M.C), and Translational Research Grant of NCRCH (NO. 2020ZKZC04 to A.-B.L.), and the Ministry of Science and Technology of China (NO. 2021YFA1100800 to A.-B.L.), and Shanghai Municipal Health Commission (NO. 2020CXJQ02 to A.-B.L.), and Guangxi Natural Science Foundation Program (NO. 2019GXNSFDA245031 and 2021GXNSFAA220097 to C.-W.D.), and the “Dawn” Program of Shanghai Education Commission (NO. 19SG14 to C.-W.D.), and the Program of Shanghai Academic/Technology Research Leader (NO. 21XD1422600 to C.-W.D.), and the Shanghai Sailing Program (NO.21YF1428200 to K.-M.C.).

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Author notes

  1. Wei-Wei Zheng, Hang Zhou and Ping Li have contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Pediatric Hematology and Oncology Ministry of Health and Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Wei-Wei Zheng, Hang Zhou, Tuersunayi Abudureheman, Li-Ting Yang, Kai-Ming Chen & Cai-Wen Duan

  2. Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China

    Hang Zhou & Cai-Wen Duan

  3. Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200092, China

    Ping Li, Shi-Guang Ye & Ai-Bin Liang

  4. State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Kai Qing

  5. Fujian Branch of Shanghai Children’s Medical Center Affiliated to Shanghai Jiaotong University School of Medicine and Fujian Children’s Hospital, Fuzhou, China

    Kai-Ming Chen & Cai-Wen Duan

  6. Key Laboratory of Technical Evaluation of Fertility Regulation for Non-Human Primate, National Health Commission, Fujian Maternity and Child Health Hospital, Fuzhou, China

    Cai-Wen Duan

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Contributions

CKM, DCW and LAB: designed the study, analyzed and interpreted data, and wrote the paper; ZWW, ZH and LP performed experiments, analyzed and interpreted experimental and clinical data; YSG collected clinical samples; AT and YLT performed experiments; QK discussed results and contributed to data interpretation. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ai-Bin Liang, Kai-Ming Chen or Cai-Wen Duan.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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The animal study was reviewed and approved by institutional ethical review process committee.

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Zheng, WW., Zhou, H., Li, P. et al. Anti-CD79b/CD3 bispecific antibody combined with CAR19-T cells for B-cell lymphoma treatment. Cancer Immunol Immunother 72, 3739–3753 (2023). https://doi.org/10.1007/s00262-023-03526-z

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