Page 117 - Haematologica Vol. 109 - July 2024

ARTICLE - Cell Therapy & Immunotherapy
Harnessing the cytotoxic granule exocytosis to augment
the efficacy of T-cell-engaging bispecific antibody therapy
Mika Casey,1 Carol Lee,1 Sharon M. Hoyte,1 Rebecca L. Johnston,1 Wing Yu Kwok,1 Soi Cheng Law,2 Maher K. Gandhi,2 Simon J. Harrison3,4 and Kyohei Nakamura1
1Cancer Research Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland; 2Mater Research, University of Queensland, Brisbane, Queensland; 3Clinical Hematology, Peter MacCallum Cancer Center and Royal Melbourne Hospital, Melbourne, Victoria and 4Sir Peter MacCallum, Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
Abstract
T-cell-engaging bispecific antibody (T-BsAb, also known as BiTE) therapy has emerged as a powerful therapeutic modality against multiple myeloma. Given that T-BsAb therapy redirects endogenous T cells to eliminate tumor cells, reinvigorating dysfunctional T cells may be a potential approach to improve the efficacy of T-BsAb. While various immunostimulatory cytokines can potentiate effector T-cell functions, the optimal cytokine treatment for T-BsAb therapy is yet to be estab- lished, partly due to a concern of cytokine release syndrome driven by aberrant interferon (IFN)-γ production. Here, we functionally screen immunostimulatory cytokines to determine an ideal combination partner for T-BsAb therapy. This ap- proach reveals interleukin (IL)-21 as a potential immunostimulatory cytokine with the ability to augment T-BsAb-mediated release of granzyme B and perforin, without increasing IFN-γ release. Transcriptome profiling and functional characteriza- tion strongly support that IL-21 selectively targets the cytotoxic granule exocytosis pathway, but not pro-inflammatory responses. Notably, IL-21 modulates multiple steps of cytotoxic effector functions including upregulation of co-activating CD226 receptor, increasing cytotoxic granules, and promoting cytotoxic granule delivery at the immunological synapse. Indeed, T-BsAb-mediated myeloma killing is cytotoxic granule-dependent, and IL-21 priming significantly augments cyto- toxic activities. Furthermore, in vivo IL-21 treatment induces cytotoxic effector reprogramming in bone marrow T cells, showing synergistic anti-myeloma effects in combination with T-BsAb therapy. Together, harnessing the cytotoxic granule exocytosis pathway by IL-21 may be a potential approach to achieve better responses by T-BsAb therapy.
Introduction
Multiple myeloma, a plasma cell neoplasm, has historically been recognized as an incurable disease. Over the past decade, the treatment landscape of multiple myeloma has dramatically evolved with T-cell redirection immunother- apies such as T-cell-engaging bispecific antibody (T-BsAb, also known as BiTE) therapy and chimeric antigen receptor (CAR) T-cell therapy.1-3 T-BsAb therapy can redirect endog- enous polyclonal T cells to recognize and eliminate tumor cells by simultaneously engaging target antigens on tumor cells and CD3 on T cells. As the cancer-immunity cycle is frequently dysregulated in multiple myeloma,4 T-BsAb therapy is recognized as a potential approach to stimulate adaptive immunity to control multiple myeloma. Recently, T-BsAb therapies targeting B-cell maturation antigen (BC- MA), G-protein coupled receptor family C group 5 member
D, and Fc Receptor-Like 5 have shown impressive clinical responses in heavily pretreated patients with relapsed/ refractory multiple myeloma.1,2,5
Despite impressive clinical responses, treatment failure and relapse remain major obstacles. Still, it remains largely unknown how we can overcome therapeutic resistance mediated by loss of target antigen, immunosuppression, and T-cell hyporesponsiveness.4,6,7 Given that T-BsAb stim- ulate endogenous T cells and that T cells are functionally impaired in the myeloma bone marrow (BM),4,8-10 repro- gramming dysfunctional T cells might be necessary to achieve better disease control by T-BsAb therapy. Indeed, in a recent preclinical study, we showed that priming of cytotoxic lymphocytes by innate immune activation can improve T-BsAb efficacy, supporting the importance of har- nessing effector T-cell functions prior to T-BsAb therapy.11 Immunostimulatory cytokines including common γ-chain
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Correspondence: K. Nakamura kyohei.nakamura@qimrberghofer.edu.au
Received: Accepted: Early view:
October 30, 2023. January 12, 2024. January 25, 2024.
https://doi.org/10.3324/haematol.2023.284435
©2024 Ferrata Storti Foundation Published under a CC BY-NC license