Please use this identifier to cite or link to this item:
|Title:||Daratumumab displays in vitro and in vivo anti-tumor activity in models of B cell non-Hodgkin lymphoma and improves responses to standard chemo-immunotherapy regimens|
|Author:||Vidal Crespo, Anna|
Matas Céspedes, Alba
Valero, Juan G.
Sanjuan Pla, Alejandra
Menéndez Buján, Pablo
López Guillermo, Armando
Giné Soca, Eva
Campo Güerri, Elias
Colomer Pujol, Dolors
Lammerts van Bueren, J.
Pérez Galán, Patricia
|Keywords:||Malaltia de Hodgkin|
|Publisher:||Ferrata Storti Foundation|
|Abstract:||CD38 is expressed in several types of non-Hodgkin lymphoma and constitutes a promising target for antibody-based therapy. Daratumumab (Darzalex) is a first-in-class anti-CD38 antibody approved for the treatment of relapsed/refractory multiple myeloma. It has also demonstrated clinical activity in Waldenstrom macroglobulinaemia and amyloidosis. Here, we have evaluated the activity and mechanism of action of daratumumab in preclinical in vitro and in vivo models of mantle cell lymphoma, follicular lymphoma and diffuse large B cell lymphoma, as monotherapy or in combination with standard chemo-immunotherapy. In vitro, daratumumab engages Fc-mediated cytotoxicity by antibody-dependent cell cytotoxicity and antibody-dependent cell phagocytosis in all lymphoma subtypes. In the presence of human serum, complement-dependent cell cytotoxicity was marginally engaged. We demonstrated by Selective Plane Illumination Microscopy that daratumumab fully penetrated a 3D lymphoma organoid and decreased organoid volume. In vivo, daratumumab completely prevents tumor outgrowth in models of mantle cell and follicular lymphoma, and shows comparable activity to rituximab in a disseminated in vivo model of blastic mantle cell lymphoma. Moreover, daratumumab improves overall survival in a mouse model of transformed CD20dim follicular lymphoma, where rituximab showed limited activity. Daratumumab potentiates the antitumor activity of CHOP and R-CHOP in mantle cell and follicular lymphoma xenografts. Furthermore, in a patient-derived diffuse large B cell lymphoma xenograft model, daratumumab anti-tumor activity was comparable to R-CHOP and the addition of daratumumab to either CHOP or R-CHOP led to full tumor regression. In summary, daratumumab constitutes a novel therapeutic opportunity in certain scenarios and these results warrant further clinical development.|
|Note:||Reproducció del document publicat a: https://doi.org/10.3324/haematol.2018.211904|
|It is part of:||Haematologica, 2019|
|Appears in Collections:||Articles publicats en revistes (Fonaments Clínics)|
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.