Page 128 - Haematologica Vol. 109 - July 2024

ARTICLE - Cytotoxic reprogramming for BiTE immunotherapy M. Casey et al.
impact on CRS, as the CRS-like phenotype is not observed in preclinical T-BsAb models. Another limitation of the current study is that this study exclusively evaluated the impact of rIL-21 on anti-BCMA T-BsAb against multiple myeloma. It is reported that IL-21 can directly induce apoptosis in B-cell lymphomas, but not in multiple myeloma, possibly by up- regulating BIM (a member of the pro-apoptotic BH3-only members protein) in B-lymphoma cells.49-51 In this context, beyond the IL-21-driven cytotoxic program, rIL-21 treatment may be able to lower the apoptotic threshold in B-lymphoma cells, leading to enhancement of anti-CD20 T-BsAb effica- cy. Further studies are warranted to understand the tumor type-specific effect of rIL-21. Lastly, it is important to address whether IL-21 can improve T-cell immunity in patients with relapsed/refractory myeloma, although T-BsAb therapy is being tested as an earlier line of therapy (clinicaltrials gov. Identifier: NCT05469893). Despite these limitations, results from this study provide important translational implications for improving the efficacy of T-BsAb therapy against multiple myeloma and other hematological malignancies.
advisory role). KN received honorariums from Janssen, Sanofi, and Bristol Myers Squibb. The other authors have no conflicts of interest to disclose.
Contributions
KN designed the research and wrote the manuscript. MC, CL, WYK and KN performed experimental work and analyzed the data. SMH and RLJ performed data analysis. SCL and MKG provided key materials. SCL, MKG and SJH contributed to critical discussion and data interpretation. KN conceived and supervised the study. All authors read and approved the final version of the manuscript.
Acknowledgments
The authors wish to thank Bristol Myers Squibb for providing anti-mouse T-BsAb. The authors also thank technical sup- port from the QIMR flow cytometry facility. We thank Ross Koufariotis and the QIMR Genome Informatics team for their help processing RNA-sequencing data.
Funding
The authors deeply appreciate funding support from the Play for a Cure Foundation. KN is supported by the NHMRC project grant (1159593) and the Naito Foundation. This proj- ect was supported by grant 2000538 awarded through the 2020 Priority-driven Collaborative Cancer Research Scheme and funded by the Leukemia Foundation with the support of Cancer Australia.
Data-sharing statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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9. Tirier SM, Mallm J-P, Steiger S, et al. Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single-cell transcriptomics. Nature Commun. 2021;12(1):6960.
10. Dhodapkar MV. The immune system in multiple myeloma and precursor states: lessons and implications for immunotherapy and interception. Am J Hematol. 2023;98(Suppl 2):S4-S12.
11. Casey M, Tu C, Harrison SJ, Nakamura K. Invariant NKT cells dictate antitumor immunity elicited by a bispecific antibody cotargeting CD3 and BCMA. Blood Adv. 2022;6(17):5165-5170.
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Disclosures
MKG reports research support unrelated to this work from Janssen and Beigene. SJH reports support unrelated to this work from AbbVie (consultancy, advisory board, investigator on studies); Amgen, Celgene, Janssen Cilag and Novartis (consultancy, honoraria, advisory board, research funding, investigator on studies); GSK (consultancy, research funding, advisory board); Roche/Genentech (consultancy, honoraria, advisory board, investigator on studies); Takeda (consultancy, honoraria, advisory board); Haemalogix (scientific advisory board, research funding, investigator); Sanofi (consultancy/
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