Skip to main content

Advertisement

SpringerLink
Log in

Coadministration with bendamustine restores the antitumor activity of obinutuzumab in obinutuzumab-resistant tumors

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Background

The glycoengineered, humanized anti-CD20 antibody obinutuzumab is indicated for previously untreated or relapsed/refractory CD20-positive follicular lymphoma (FL). However, the effectiveness of obinutuzumab retreatment in relapsed/refractory FL after prior obinutuzumab-containing therapy is unclear. To address this issue, we investigated the antitumor activity of obinutuzumab plus bendamustine in obinutuzumab-resistant tumors established from a human non-Hodgkin lymphoma xenograft model.

Materials and methods

Obinutuzumab-resistant tumors (SU-DHL-4-OR-18-8) were established from an SU-DHL-4 xenograft model by repeated administration of obinutuzumab. Antitumor activity was evaluated based on tumor volume after treatment with obinutuzumab on Day 1, 8, and 15 and/or bendamustine on Day 1 and 2. Intratumoral natural killer (NK) cells/macrophages were evaluated by immunohistochemistry and flow cytometry.

Results

In SU-DHL-4-OR-18-8 xenografted tumors, intratumoral NK cells/macrophages after obinutuzumab treatment were significantly decreased compared with parent tumors on Day 4. The endoplasmic reticulum stress sensor phospho-IRE1 was also decreased. In SU-DHL-4-OR-18-8 tumors, bendamustine treatment increased phospho-IRE1 on Day 4 and intratumor NK cells/macrophages on Day 10. Obinutuzumab combined with bendamustine significantly increased antitumor activity compared with each single agent on Day 29, with an increase in chemoattractant CCL6 expression on Day 10.

Conclusions

Coadministration of bendamustine in obinutuzumab retreatment may be effective against obinutuzumab-resistant tumors.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Freedman A, Jacobsen E. Follicular lymphoma: 2020 update on diagnosis and management. Am J Hematol. 2020;95:316–27.

    Article  CAS  Google Scholar 

  2. Apostolidis J, Mokhtar N, Al Omari R, Darweesh M, Al Hashmi H. Follicular lymphoma: update on management and emerging therapies at the dawn of the new decade. Hematol Oncol. 2020;38:213–22.

    Article  Google Scholar 

  3. Rivas-Delgado A, Magnano L, Moreno-Velázquez M, García O, Nadeu F, Mozas P, et al. Response duration and survival shorten after each relapse in patients with follicular lymphoma treated in the rituximab era. Br J Haematol. 2019;184:753–9.

    Article  CAS  Google Scholar 

  4. Goede V, Klein C, Stilgenbauer S. Obinutuzumab (GA101) for the treatment of chronic lymphocytic leukemia and other B-cell non-hodgkin’s lymphomas: a glycoengineered type II CD20 antibody. Oncol Res Treat. 2015;38:185–92.

    Article  CAS  Google Scholar 

  5. Mössner E, Brünker P, Moser S, Püntener U, Schmidt C, Herter S, et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 2010;115:4393–402.

    Article  Google Scholar 

  6. Bakema JE, van Egmond M. Fc receptor-dependent mechanisms of monoclonal antibody therapy of cancer. Curr Top Microbiol Immunol. 2014;382:373–92.

    CAS  PubMed  Google Scholar 

  7. Trotman J, Barrington SF, Belada D, Meignan M, MacEwan R, Owen C, et al. Prognostic value of end-of-induction PET response after first-line immunochemotherapy for follicular lymphoma (GALLIUM): secondary analysis of a randomised, phase 3 trial. Lancet Oncol. 2018;19:1530–42.

    Article  CAS  Google Scholar 

  8. Sehn LH, Chua N, Mayer J, Dueck G, Trněný M, Bouabdallah K, 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;17:1081–93.

    Article  CAS  Google Scholar 

  9. Hanovich E, Asmis T, Ong M, Stewart D. Rechallenge strategy in cancer therapy. Oncology. 2020;98:669–79.

    Article  CAS  Google Scholar 

  10. Davis TA, Grillo-López AJ, White CA, McLaughlin P, Czuczman MS, Link BK, et al. Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin’s lymphoma: Safety and efficacy of re-treatment. J Clin Oncol. 2000;18:3135–43.

    Article  CAS  Google Scholar 

  11. Johnston A, Bouafia-Sauvy F, Broussais-Guillaumot F, Michallet AS, Traullé C, Salles G, et al. Retreatment with rituximab in 178 patients with relapsed and refractory B-cell lymphomas: a single institution case control study. Leuk Lymphoma. 2010;51:399–405.

    Article  CAS  Google Scholar 

  12. Fujimura T, Yamashita-Kashima Y, Kawasaki N, Yoshiura S, Harada N, Yoshimura Y. Obinutuzumab in combination with chemotherapy enhances direct cell death in CD20-positive obinutuzumab-resistant non-hodgkin lymphoma cells. Mol Cancer Ther. 2021;20:1133–41.

    Article  CAS  Google Scholar 

  13. Arantes-Rodrigues R, Colaço A, Pinto-Leite R, Oliveira PA. In vitro and in vivo experimental models as tools to investigate the efficacy of antineoplastic drugs on urinary bladder cancer. Anticancer Res. 2013;33:1273–96.

    CAS  PubMed  Google Scholar 

  14. Herting F, Friess T, Bader S, Muth G, Hölzlwimmer G, Rieder N, et al. Enhanced anti-tumor activity of the glycoengineered type II CD20 antibody obinutuzumab (GA101) in combination with chemotherapy in xenograft models of human lymphoma. Leuk Lymphoma. 2014;55:2151–5160.

    Article  CAS  Google Scholar 

  15. Sehn LH, Goy A, Offner FC, Martinelli G, Caballero MD, Gadeberg O, et al. Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: final analysis of the GAUSS study. J Clin Oncol. 2015;33:3467–74.

    Article  CAS  Google Scholar 

  16. Hiraga J, Tomita A, Sugimoto T, Shimada K, Ito M, Nakamura S, et al. Down-regulation of CD20 expression in B-cell lymphoma cells after treatment with rituximab-containing combination chemotherapies: its prevalence and clinical significance. Blood. 2009;113:4885–93.

    Article  CAS  Google Scholar 

  17. Orlofsky A, Berger MS, Prystowsky MB. Novel expression pattern of a new member of the MIP-1 family of cytokine-like genes. Cell Regul. 1991;2:403–12.

    Article  CAS  Google Scholar 

  18. Bach LA. Recent insights into the actions of IGFBP-6. J Cell Commun Signal. 2015;9:189–200.

    Article  Google Scholar 

  19. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997;88:277–85.

    Article  CAS  Google Scholar 

  20. Coelho AL, Schaller MA, Benjamim CF, Orlofsky AZ, Hogaboam CM, Kunkel SL. The chemokine CCL6 promotes innate immunity via immune cell activation and recruitment. J Immunol. 2007;179:5474–82.

    Article  CAS  Google Scholar 

  21. Asensio VC, Lassmann S, Pagenstecher A, Steffensen SC, Henriksen SJ, Campbell IL. C10 is a novel chemokine expressed in experimental inflammatory demyelinating disorders that promotes recruitment of macrophages to the central nervous system. Am J Pathol. 1999;154:1181–91.

    Article  CAS  Google Scholar 

  22. Berger MS, Taub DD, Orlofsky A, Kleyman TR, Coupaye-Gerard B, Eisner D, et al. The chemokine C10: immunological and functional analysis of the sequence encoded by the novel second exon. Cytokine. 1996;8:439–47.

    Article  CAS  Google Scholar 

  23. LaFleur AM, Lukacs NW, Kunkel SL, Matsukawa A. Role of CC chemokine CCL6/C10 as a monocyte chemoattractant in a murine acute peritonitis. Mediat Inflamm. 2004;13:349–55.

    Article  CAS  Google Scholar 

  24. Latour S, Zanese M, Le Morvan V, Vacher AM, Menard N, Bijou F, et al. Role of calcium signaling in GA101-induced cell death in malignant human B cells. Cancers (Basel). 2019;11:291.

    Article  CAS  Google Scholar 

  25. Wu Chuang A, Kepp O, Kroemer G, Bezu L. Endoplasmic reticulum stress in the cellular release of damage-associated molecular patterns. Int Rev Cell Mol Biol. 2020;350:1–28.

    Article  Google Scholar 

  26. Krysko DV, Garg AD, Kaczmarek A, Krysko O, Agostinis P, Vandenabeele P. Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer. 2012;12:860–75.

    Article  CAS  Google Scholar 

  27. Ahmed A, Tait SWG. Targeting immunogenic cell death in cancer. Mol Oncol. 2020;14:2994–3006.

    Article  CAS  Google Scholar 

  28. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11:889–96.

    Article  CAS  Google Scholar 

  29. Burgess M, Chen YCE, Mapp S, Mollee P, Gill D, Saunders NA. Identifying an obinutuzumab resistant subpopulation of monocyte-derived-macrophages from patients with CLL. Leuk Lymphoma. 2020;61:2738–42.

    Article  CAS  Google Scholar 

  30. Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol. 2010;22:231–7.

    Article  CAS  Google Scholar 

  31. Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39–51.

    Article  CAS  Google Scholar 

  32. Guo H, Liu Y, Gu J, Wang Y, Liu L, Zhang P, et al. Endostatin inhibits the growth and migration of 4T1 mouse breast cancer cells by skewing macrophage polarity toward the M1 phenotype. Cancer Immunol Immunother. 2016;65:677–88.

    Article  CAS  Google Scholar 

  33. Liu X, Nie W, Xie Q, Chen G, Li X, Jia Y, et al. Endostatin reverses immunosuppression of the tumor microenvironment in lung carcinoma. Oncol Lett. 2018;15:1874–80.

    PubMed  Google Scholar 

  34. Zhu J, Lou Y, Liu P, Xu LX. Tumor-related HSP70 released after cryo-thermal therapy targeted innate immune initiation in the antitumor immune response. Int J Hyperth. 2020;37:843–53.

    Article  CAS  Google Scholar 

  35. Kawasaki N, Yamashita-Kashima Y, Fujimura T, Yoshiura S, Harada N, Kondoh O, et al. Resistance to obinutuzumab-induced antibodydependent cellular cytotoxicity caused by abnormal Fas signaling is overcome by combination therapies. Mol Biol Rep. 2022; (Online ahead of print).

  36. Gastpar R, Gross C, Rossbacher L, Ellwart J, Riegger J, Multhoff G. The cell surface-localized heat shock protein 70 epitope TKD induces migration and cytolytic activity selectively in human NK cells. J Immunol. 2004;172:972–80.

    Article  CAS  Google Scholar 

  37. Lossos C, Liu Y, Kolb KE, Christie AL, Van Scoyk A, Prakadan SM, et al. Mechanisms of lymphoma clearance induced by high-dose alkylating agents. Cancer Discov. 2019;9:944–61.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. Yoshiaki Isshiki, Dr. Kazushige Mori, and Dr. Kaori Fujimoto-Ouchi (all from Chugai Pharmaceutical Co., Ltd.) for their helpful advice, and Ms. Masako Miyazaki, Ms. Hiromi Sawamura, and Ms. Ikuno Sugimoto (all from Chugai Pharmaceutical Co., Ltd.) for their excellent technical assistance with the experiments.

Funding

Funding was provided by Chugai Pharmaceutical Co., Ltd. and Nippon Shinyaku Co., Ltd.

Author information

Authors and Affiliations

  1. Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan

    Yoriko Yamashita-Kashima, Keigo Yorozu, Takaaki Fujimura, Natsumi Kawasaki, Mitsue Kurasawa, Shigeki Yoshiura, Naoki Harada, Osamu Kondoh & Yasushi Yoshimura

Authors
  1. Yoriko Yamashita-Kashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keigo Yorozu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takaaki Fujimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Natsumi Kawasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mitsue Kurasawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shigeki Yoshiura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Naoki Harada
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Osamu Kondoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yasushi Yoshimura
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YYK established the study concept, conceived the idea, designed and performed the experiments, analyzed the data, and prepared the manuscript. NH, OK, and YY supervised the study and conducted critical revision to the manuscript. KY, TF, and MK performed the experiments. TF, NK, and SY interpreted the results and reviewed and revised the manuscript. All authors contributed to the final manuscript and approved it for submission.

Corresponding author

Correspondence to Yoriko Yamashita-Kashima.

Ethics declarations

Conflict of interest

All authors are employees of Chugai Pharmaceutical Co., Ltd. This research was funded by Chugai Pharmaceutical Co., Ltd. and Nippon Shinyaku Co., Ltd.

Ethics approval and consent to participate

All animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee at Chugai Pharmaceutical Co., Ltd. (approval numbers: 17-122, 18-042, 19-139 and 19-329).

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (TIF 7337 KB)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yamashita-Kashima, Y., Yorozu, K., Fujimura, T. et al. Coadministration with bendamustine restores the antitumor activity of obinutuzumab in obinutuzumab-resistant tumors. Int J Hematol 115, 860–872 (2022). https://doi.org/10.1007/s12185-022-03320-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-022-03320-0

Keywords

Search

Navigation