Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab.

I S Nijhof,W A Noort,A C M Martens,R De Jong-Korlaar,A C Bloem,H M Lokhorst,S K Klein,T Mutis,R W J Groen,K Sasser,B Van Kessel,P Doshi,N W C J Van De Donk,H Yuan,J Van Velzen

doi:10.1038/leu.2015.123

Abstract

Daratumumab is an anti-CD38 monoclonal antibody with lytic activity against multiple myeloma (MM) cells, including ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent cytotoxicity). Owing to a marked heterogeneity of response to daratumumab therapy in MM, we investigated determinants of the sensitivity of MM cells toward daratumumab-mediated ADCC and CDC. In bone marrow samples from 144 MM patients, we observed no difference in daratumumab-mediated lysis between newly diagnosed or relapsed/refractory patients. However, we discovered, next to an expected effect of effector (natural killer cells/monocytes) to target (MM cells) ratio on ADCC, a significant association between CD38 expression and daratumumab-mediated ADCC (127 patients), as well as CDC (56 patients). Similarly, experiments with isogenic MM cell lines expressing different levels of CD38 revealed that the level of CD38 expression is an important determinant of daratumumab-mediated ADCC and CDC. Importantly, all-trans retinoic acid (ATRA) increased CD38 expression levels but also reduced expression of the complement-inhibitory proteins CD55 and CD59 in both cell lines and primary MM samples. This resulted in a significant enhancement of the activity of daratumumab in vitro and in a humanized MM mouse model as well. Our results provide the preclinical rationale for further evaluation of daratumumab combined with ATRA in MM patients.

Highlights

The introduction of autologous stem cell transplantation as well as novel agents such as bortezomib and the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide has significantly improved long-term outcome of multiple myeloma (MM) patients.[1]
We evaluated daratumumabmediated complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) against primary MM cells, in relation to CD38 expression on the tumor cells, frequency of effector cells in the bone marrow and extent of previous treatment of the patient
The importance of CD38 expression was further strengthened by the observation that an enforced increase in CD38 expression levels on UM9 and L363 cells resulted in an increase in daratumumab-mediated CDC and ADCC

Summary

Introduction

The introduction of autologous stem cell transplantation as well as novel agents such as bortezomib and the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide has significantly improved long-term outcome of multiple myeloma (MM) patients.[1]. Patients with lenalidomide and bortezomib-refractory MM have a very poor outcome with a median overall survival of only 9 months.[2]. This clearly demonstrates that there is a need for new treatment approaches, especially for these categories of patients. In this respect, several new antimyeloma agents hold promise, including next-generation IMiDs (pomalidomide) and proteasome inhibitors (carfilzomib), and compounds with different mechanisms of action.[3,4]. CD38 is a type II transmembrane glycoprotein with ectoenzymatic activity involved in the catabolism of extracellular nucleotides.[7,8] Other functions ascribed to CD38 include receptor-mediated adhesion by interacting with CD31 or hyaluronic acid, regulation of migration and signaling events.[7,8,9,10]

Methods

Results

Conclusion