@article{2a6a9a89c4394de9a11204a56c6290be,
title = "Venetoclax treatment in patients with cancer has limited impact on circulating T and NK cells",
abstract = "Venetoclax is an effective treatment for certain blood cancers, such as chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, most patients relapse while on venetoclax and further treatment options are limited. Combining venetoclax with immunotherapies is an attractive approach; however, a detailed understanding of how venetoclax treatment impacts normal immune cells in patients is lacking. In this study, we performed deep profiling of peripheral blood (PB) cells from patients with CLL and AML before and after short-term treatment with venetoclax using mass cytometry (cytometry by time of flight) and found no impact on the concentrations of key T-cell subsets or their expression of checkpoint molecules. We also analyzed PB from patients with breast cancer receiving venetoclax long-term using a single-cell multiomics approach (cellular indexing of transcriptomes and epitopes by sequencing) and functional assays. We found significant depletion of B-cell populations with low expression of MCL-1 relative to other immune cells, attended by extensive transcriptomic changes. By contrast, there was less impact on circulating T cells and natural killer (NK) cells, with no changes in their subset composition, transcriptome, or function following venetoclax treatment. Our data indicate that venetoclax has minimal impact on circulating T or NK cells, supporting the rationale of combining this BH3 mimetic drug with cancer immunotherapies for more durable antitumor responses.",
author = "Teh, {Charis E.} and Hongke Peng and Luo, {Meng Xiao} and Tania Tan and Marie Trussart and Howson, {Lauren J.} and Chua, {Chong Chyn} and Christine Muttiah and Fiona Brown and Ritchie, {Matthew E.} and Wei, {Andrew H.} and Roberts, {Andrew W.} and Bryant, {Vanessa L.} and Anderson, {Mary Ann} and Lindeman, {Geoffrey J.} and Huang, {David C.S.} and Rachel Thijssen and Gray, {Daniel H.D.}",
note = "Funding Information: This work was supported by grants and fellowships from the Australian National Health and Medical Research Council (NHMRC) fellowships (1089072) (C.E.T.), (1090236 and 1158024) (D.H.D.G.), (1078730 and 1175960) (G.J.L.), (1079560) (A.W.R.), and (1043149 and 1156024) (D.C.S.H.); Investigator grants (1177718) (M.-A.A.), (1174902) (A.W.R.), and (2007884) (L.J.H.); a Fulbright Australia-America Postdoctoral Fellowship (C.E.T.); Victorian Cancer Agency Fellowships (MCRF20026) (C.E.T.) and (ECRF21014) (R.T.); Sir Clive McPherson Family Research Fellowship (V.L.B.); Cancer Council of Victoria Grants-in-Aid (1146518 and 1102104) (D.H.D.G.); Perpetual Impact Philanthropy funding (C.E.T.); Australian NHRMC grants (2002618) (C.E.T.), (1016647, 1113577, 1016701, 1113133, and 1079560) (A.W.R. and D.C.S.H.), (1113133 and 1153049) (G.J.L.), (2013478) (D.C.S.H. and R.T.), and the Metcalf Family (A.H.W.); the Leukemia and Lymphoma Society, US, Specialized Center of Research grant (7015-18) (A.H.W., A.W.R., and D.C.S.H.); a Medical Research Future Fund grant (1141460) (A.H.W.); National Breast Cancer Foundation Australia (IIRS-19-004); Breast Cancer Research Foundation (BCRF-20-182) (G.J.L.); Rae Foundation (V.L.B.); Jack Brockhoff Foundation Early Career Research grant (JBF4847-2021) (L.J.H.); University of Melbourne Melbourne Research Scholarship and Melbourne International Fee Remission Scholarship (H.P.); and Investigator Initiated Study support from AbbVie and Genentech (Roche) for the breast cancer study (#ACTRN12615000702516) (G.J.L). Funding Information: This work was performed in part at the Materials Characterisation and Fabrication Platform at the University of Melbourne and the Victorian Node of the Australian National Fabrication Facility with support from the Victorian Comprehensive Cancer Centre. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institutes Infrastructure Support Scheme. Funding Information: Conflict-of-interest disclosure: The Walter and Eliza Hall Institute of Medical Research receives milestone and royalty payments related to venetoclax. Employees are entitled to receive benefits related to these payments; C.E.T., H.P., M.L., T.T., M.T., C.M., F.B., M.E.R., L.J.H., V.L.B., A.H.W., A.W.R., M.-A.A., G.J.L., D.C.S.H., R.T., and D.H.D.G. report receiving these benefits. A.W.R. holds a patent related to venetoclax. G.J.L. has had a consulting/advisory role with AbbVie and Pfizer; has received research funding from Amgen and Servier; and institutional Funding Information: The authors thank Naomi Sprigg, Kirsten Hogg, Elliot Surgenor, and the Victorian Cancer Biobank for sample coordination and technical assistance; Andrew Mitchell and Tian Zheng (University of Melbourne) for assistance with mass cytometry maintenance/operation; Terence Speed for advice on data visualization; and Emma Carrington for critical review of the manuscript. This work was supported by grants and fellowships from the Australian National Health and Medical Research Council (NHMRC) fellowships (1089072) (C.E.T.), (1090236 and 1158024) (D.H.D.G.), (1078730 and 1175960) (G.J.L.), (1079560) (A.W.R.), and (1043149 and 1156024) (D.C.S.H.); Investigator grants (1177718) (M.-A.A.), (1174902) (A.W.R.), and (2007884) (L.J.H.); a Fulbright Australia-America Postdoctoral Fellowship (C.E.T.); Victorian Cancer Agency Fellowships (MCRF20026) (C.E.T.) and (ECRF21014) (R.T.); Sir Clive McPherson Family Research Fellowship (V.L.B.); Cancer Council of Victoria Grants-in-Aid (1146518 and 1102104) (D.H.D.G.); Perpetual Impact Philanthropy funding (C.E.T.); Australian NHRMC grants (2002618) (C.E.T.), (1016647, 1113577, 1016701, 1113133, and 1079560) (A.W.R. and D.C.S.H.), (1113133 and 1153049) (G.J.L.), (2013478) (D.C.S.H. and R.T.), and the Metcalf Family (A.H.W.); the Leukemia and Lymphoma Society, US, Specialized Center of Research grant (7015-18) (A.H.W., A.W.R., and D.C.S.H.); a Medical Research Future Fund grant (1141460) (A.H.W.); National Breast Cancer Foundation Australia (IIRS-19-004); Breast Cancer Research Foundation (BCRF-20-182) (G.J.L.); Rae Foundation (V.L.B.); Jack Brockhoff Foundation Early Career Research grant (JBF4847-2021) (L.J.H.); University of Melbourne Melbourne Research Scholarship and Melbourne International Fee Remission Scholarship (H.P.); and Investigator Initiated Study support from AbbVie and Genentech (Roche) for the breast cancer study (#ACTRN12615000702516) (G.J.L). Publisher Copyright: {\textcopyright} 2023 by The American Society of Hematology.",
year = "2023",
month = jun,
doi = "10.1182/bloodadvances.2022008221",
language = "English",
volume = "7",
pages = "2733--2745",
journal = "Blood Advances",
issn = "2473-9529",
publisher = "American Society of Hematology",
number = "12",
}
