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Haematologica. 2019 Jul 11. pii: haematol.2018.211904. doi: 10.3324/haematol.2018.211904. [Epub ahead of print]

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 information

1
Institut d'Investigacions Biomediques (IDIBAPS).
2
Institut d'Investigacions Biomediques (IDIBAPS); Centro de Investigacion Biomedica en Red CIBERONC.
3
Institut d'Investigacions Biomediques (IDIBAPS); Centro de Investigacion Biomedica en Red-CIBERONC.
4
Centre de Recherches en Cancerologie de Toulouse (CRCT).
5
Josep Carreras Leukemia Research Institute.
6
Josep Carreras Leukemia Research Institute; CIBERONC; ICREA.
7
Vall Hebron University Hospital.
8
Hospital Clinic-IDIBAPS; Centro de Investigacion Biomedica en Red-CIBERONC.
9
Genmab; Current affiliation: Merus.
10
Janssen R&D.
11
Institut Investigacions Biomediques (IDIBAPS); Centro de Investigacion Biomedica en Red CIBERONC pperez@clinic.ub.es.

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.

KEYWORDS:

CD38; daratumumab; diffuse large B cell lymphoma; follicular lymphoma; mantle cell lymphoma

PMID:
31296574
DOI:
10.3324/haematol.2018.211904
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