Anti-CD38 Therapy with Daratumumab for Relapsed/Refractory CD20-Negative Diffuse Large B-Cell Lymphoma

Vockova, P.; Svaton, M.; Karolova, J.; Pokorna, E.; Vokurka, Martin; Klener, Pavel

doi:10.14712/fb2020066010017

Folia Biologica > Archive > 2020, Vol. 66 > Issue 1 > Anti-CD38 Therapy with Daratumumab for…

Fol. Biol. 2020, 66, 17-23

https://doi.org/10.14712/fb2020066010017

Anti-CD38 Therapy with Daratumumab for Relapsed/Refractory CD20-Negative Diffuse Large B-Cell Lymphoma

P. Vockova^1,2, M. Svaton³, J. Karolova^1,2, E. Pokorna², Martin Vokurka², Pavel Klener^1,2

¹1st Department of Medicine – Department of Haematology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic
²Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
³CLIP – Laboratory Centre Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic

Received October 2019
Accepted January 2020

Diffuse large B-cell lymphoma (DLBCL) is the most common and one of the most aggressive subtypes of non-Hodgkin’s lymphomas. Front-line therapy consists of chemotherapy in combination with anti-CD20 monoclonal antibody rituximab. Relapses after rituximab-based regimen have poor prognosis and call for new treatment options. Immunohistochemistry analysis of relapsed DLBCL often reveal CD20-negative lymphoma, which limits repeated use of rituximab in combination with salvage chemotherapy. CD38 is a surface antigen that binds to CD38, CD31/PECAM-1 and hyaluronic acid. CD38 is an important mediator of signal transmission from the microenvironment into the cell. Anti-CD38 monoclonal antibody daratumumab has been approved for the treatment of multiple myeloma. Expression of CD38 on the surface of DLBCL is highly variable (compared to strong expression on myeloma cells), but can be easily assessed by flow cytometry or immunohistochemistry. A patient-derived xenograft (PDX) model of CD20-negative, CD38-positive DLBCL derived from a patient with rituximab-refractory DLBCL was used for in vivo experiments. We demonstrated that daratumumab suppressed growth of subcutaneous PDX tumours significantly more effectively than rituximab. Analysis of tumours obtained from mice treated with daratumumab revealed down-regulation of surface CD38, suggesting endocytosis of CD38-daratumumab complexes. The results suggest a potential clinical use of daratumumab in combination with salvage chemotherapy in patients with relapses of CD20-negative DLBCL. In addition, daratumumab might potentially serve as a suitable antibody moiety for derivation of antibodydrug conjugates for the targeted delivery of toxic payloads to the lymphoma cells.

Keywords

Non-Hodgkin lymphomas, CD38, daratumumab, patient-derived xenograft.

Funding

Financial Support from: Charles University Grant Agency, Research Grant GA-UK 250421; Czech Ministry of Education, Youth and Sports, Institutional Support PROGRES Q26/LF1 and PROGRES Q28/LF1; Charles University Centre of Excellence UNCE/MED/016; Specific University Research Programme SVV 260371.