Harnessing the cytotoxic granule exocytosis to augment the efficacy of T-cell-engaging bispecific antibody therapy

Casey, M; Lee, C; Hoyte, SM; Johnston, RL; Kwok, WY; Law, SC; Gandhi, MK; Harrison, SJ; Nakamura, K

Author(s): Casey, M; Lee, C; Hoyte, SM; Johnston, RL; Kwok, WY; Law, SC; Gandhi, MK; Harrison, SJ; Nakamura, K;
Details: Publication Year 2024-07-01,Volume 109,Issue #7,Page 2131-2143
Journal Title: Haematologica
Publication Type: Research article
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 established, 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 approach 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 characterization 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 cytotoxic 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.
Publisher: Ferrata-Storti Foundation
Keywords: *Antibodies, Bispecific/pharmacology/therapeutic use; Humans; Mice; Animals; *Multiple Myeloma/immunology/drug therapy/therapy/pathology; *Exocytosis; Cytotoxicity, Immunologic; Interleukins/metabolism; Cell Line, Tumor; Cytokines/metabolism; T-Lymphocytes, Cytotoxic/immunology/drug effects; Granzymes/metabolism; T-Lymphocytes/immunology/metabolism/drug effects
Department(s): Clinical Haematology
Publisher's Version: https://doi.org/10.3324/haematol.2023.284435
Open Access at Publisher's Site: https://doi.org/10.3324/haematol.2023.284435
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-07-30 06:33:46

Last Modified: 2024-07-30 06:34:36