Page 190 - Haematologica April 2020

Non Hodgkin Lymphoma
Ferrata Storti Foundation
Haematologica 2020 Volume 105(4):1032-1041
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
Anna Vidal-Crespo,1* Alba Matas-Céspedes,1,2*,a Vanina Rodriguez,1
Cédric Rossi,3 Juan G. Valero,1,2 Neus Serrat,1,2 Alejandra Sanjuan-Pla,4 Pablo Menéndez,2,4,5 Gaël Roué,6 Armando López-Guillermo,2,7 Eva Giné,2,7 Elías Campo,2,8,9 Dolors Colomer,2,8 Christine Bezombes,10 Jeroen Lammerts van Bueren,11,b Christopher Chiu,12 Parul Doshi12,c and Patricia Pérez-Galán1,2
aCurrent affiliation: Grifols, Barcelona, Spain; bCurrent affiliation: Merus, Utrecht, The Netherlands; cCurrent affiliation: Bristol Myers Squibb, Lawrenceville, NJ, USA
1Department of Hematology-Oncology, Institut d'Investigacions Biomèdiques August
Pi i Sunyer (IDIBAPS), Barcelona, Spain; 2Centro de Investigación Biomédica en Red-Oncología (CIBERONC), Barcelona, Spain; 3Department of Hematology, Dijon University Hospital, Dijon, France; 4Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain; 5Instituciò Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain; 6Laboratory of Experimental Hematology, Department of Hematology, Vall d'Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, Spain; 7Department of Hematology, Hospital Clínic-IDIBAPS, Barcelona, Spain; 8Hematopathology Unit, Department of Pathology, Hospital Clínic-IDIBAPS, Barcelona, Spain; 9Faculty of Medicine, University of Barcelona, Barcelona Spain; 10Centre de Recherches en Cancérologie de Toulouse (CRCT), UMR1037 INSERM, Université Toulouse III: Paul-Sabatier, ERL5294 CNRS, Université de Toulouse, Toulouse, France;
11Genmab, Utrecht, the Netherlands and 12Janssen R&D, Spring House, PA, USA *AV-C and AM-C contributed equally to this work.
ABSTRACT
CD38 is expressed in several types of non-Hodgkin lymphoma (NHL) 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 (R/R) multiple myeloma (MM). It has also demonstrated clinical activity in Waldenström macroglob- ulinaemia and amyloidosis. Here, we have evaluated the activity and mech- anism of action of daratumumab in preclinical in vitro and in vivo models of mantle cell lymphoma (MCL), follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), as monotherapy or in combination with stan- dard chemo-immunotherapy. In vitro, daratumumab engages Fc-mediated cytotoxicity by antibody-dependent cell cytotoxicity and antibody-depen- dent 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 daratu- mumab fully penetrated a three-dimensional (3D) lymphoma organoid and decreased organoid volume. In vivo, daratumumab completely prevents tumor outgrowth in models of MCL and FL, and shows comparable activity to rituximab in a disseminated in vivo model of blastic MCL. Moreover, daratumumab improves overall survival (OS) in a mouse model of trans- formed CD20dim FL, where rituximab showed limited activity. Daratumumab potentiates the antitumor activity of CHOP and R-CHOP in MCL and FL xenografts. Furthermore, in a patient-derived DLBCL 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 fur- ther clinical development.
Correspondence:
PATRICIA PÉREZ-GALÁN
pperez@clinic.cat
Received: November 13, 2018. Accepted: July 9, 2019. Pre-published: July 11, 2019.
doi:10.3324/haematol.2018.211904
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/4/1032
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