Research output: Contribution to journal › Article › Academic › peer-review
Co-stimulatory versus cell death aspects of agonistic cd40 monoclonal antibody selicrelumab in chronic lymphocytic leukemia. / Delgado, Raquel; Kielbassa, Karoline; ter Burg, Johanna et al.
In: Cancers, Vol. 13, No. 12, 3084, 02.06.2021.Research output: Contribution to journal › Article › Academic › peer-review
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TY - JOUR
T1 - Co-stimulatory versus cell death aspects of agonistic cd40 monoclonal antibody selicrelumab in chronic lymphocytic leukemia
AU - Delgado, Raquel
AU - Kielbassa, Karoline
AU - ter Burg, Johanna
AU - Klein, Christian
AU - Trumpfheller, Christine
AU - de Heer, Koen
AU - Kater, Arnon P.
AU - Eldering, Eric
N1 - Funding Information: Funding: This work was supported by Roche Innovation Center Zurich. RD was supported by a grant from Foundation for Science and Technology (FCT, Portugal) and partially supported by the PGCD - Graduate Program Science for Development. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/6/2
Y1 - 2021/6/2
N2 - Objectives: Chronic lymphocytic leukemia (CLL) is a common form of leukemia with a heterogeneous clinical course that remains incurable due to the development of therapy resistance. In lymph node proliferation centers, signals from the microenvironment such as CD40 ligation through interaction with follicular T helper cells shield CLL cells from apoptosis. Previous observations have shown that, despite CD40-induced changes in apoptotic mediators resulting in cell survival, CD40 activation also increases sensitivity to cell death by CD20 mAbs rituximab and obinutuzumab. To further investigate these observations, we here studied the activity of the fully human agonistic CD40 mAb selicrelumab in primary CLL cells in relation to cell activation, induced pro-survival profile, and sensitization for cell death by aCD20 mAbs, in vitro. Methods: CLL cells from peripheral blood were isolated by the Ficoll density method. The expression of activation markers and cytokine production following CD40 stimulation was quantified by flow cytometry and ELISA. The anti-apoptotic profile of CLL induced by stimulation was evaluated by the expression of BCL-2 proteins with Western blot, and resistance to venetoclax with flow cytometry. Cell death induced by the combination of selicrelumab and aCD20 mAbs was quantified by flow cytometry. Results: CLL cells treated with selicrelumab upregulated co-stimulatory molecules such as CD86, TNF-α and death receptor CD95/Fas. In contrast to the CD40 ligand-transfected NIH3T3 cells, induction of resistance to venetoclax by selicrelumab was very moderate. Importantly, selicrelumab stimulation positively sensitized CLL cells to CD20-induced cell death, comparable to CD40 ligand-transfected NIH3T3 cells. Conclusions: Taken together, these novel insights into selicrelumab-stimulatory effects in CLL may be considered for developing new therapeutic strategies, particularly in combination with obinutuzumab.
AB - Objectives: Chronic lymphocytic leukemia (CLL) is a common form of leukemia with a heterogeneous clinical course that remains incurable due to the development of therapy resistance. In lymph node proliferation centers, signals from the microenvironment such as CD40 ligation through interaction with follicular T helper cells shield CLL cells from apoptosis. Previous observations have shown that, despite CD40-induced changes in apoptotic mediators resulting in cell survival, CD40 activation also increases sensitivity to cell death by CD20 mAbs rituximab and obinutuzumab. To further investigate these observations, we here studied the activity of the fully human agonistic CD40 mAb selicrelumab in primary CLL cells in relation to cell activation, induced pro-survival profile, and sensitization for cell death by aCD20 mAbs, in vitro. Methods: CLL cells from peripheral blood were isolated by the Ficoll density method. The expression of activation markers and cytokine production following CD40 stimulation was quantified by flow cytometry and ELISA. The anti-apoptotic profile of CLL induced by stimulation was evaluated by the expression of BCL-2 proteins with Western blot, and resistance to venetoclax with flow cytometry. Cell death induced by the combination of selicrelumab and aCD20 mAbs was quantified by flow cytometry. Results: CLL cells treated with selicrelumab upregulated co-stimulatory molecules such as CD86, TNF-α and death receptor CD95/Fas. In contrast to the CD40 ligand-transfected NIH3T3 cells, induction of resistance to venetoclax by selicrelumab was very moderate. Importantly, selicrelumab stimulation positively sensitized CLL cells to CD20-induced cell death, comparable to CD40 ligand-transfected NIH3T3 cells. Conclusions: Taken together, these novel insights into selicrelumab-stimulatory effects in CLL may be considered for developing new therapeutic strategies, particularly in combination with obinutuzumab.
KW - ACD20 immunotherapy
KW - CD40 activation
KW - CLL
KW - Venetoclax
UR - http://www.scopus.com/inward/record.url?scp=85108173031&partnerID=8YFLogxK
U2 - 10.3390/cancers13123084
DO - 10.3390/cancers13123084
M3 - Article
C2 - 34205588
VL - 13
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 12
M1 - 3084
ER -
ID: 18757940