Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repe

Abstract:

Jakub Krejcik,1,2, * Tineke Casneuf,3, * Inger S. Nijhof,1 Bie Verbist,3 Jaime Bald,4 Torben Plesner,2 Khaja Syed,4 Kevin Liu,5 Niels W. C. J. van de Donk,1 Brendan M. Weiss,6 Tahamtan Ahmadi,4 Henk M. Lokhorst,1 Tuna Mutis,1, † and A. Kate Sasser4, †

1Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands; 2Institute of Regional Health Science and Department of

Hematology, Sections of Internal Medicine, Vejle Hospital and University of Southern Denmark, Vejle, Denmark; 3Janssen Research & Development,

Beerse, Belgium; 4Janssen Research & Development, LLC, Spring House, PA; 5Janssen Research & Development, LLC, Raritan, NJ; and 6Division of

Hematology-Oncology, Department of Medicine, Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

Daratumumab targets CD38-expressing myeloma cells through a variety of immune mediated mechanisms (complement-dependent cytotoxicity, antibody-dependent cell mediated cytotoxicity, and antibody-dependent cellular phagocytosis) and direct apoptosis with crosslinking. These mechanisms may also target nonplasma cells that express CD38, which prompted evaluation of daratumumab’s effects on CD38-positive immune subpopulations. Peripheral blood (PB) and bone marrow (BM) from patients with relapsed/refractory myeloma from 2 daratumumab monotherapy studies were analyzed before and during therapy and at relapse. Regulatory B cells and myeloid-derived suppressor cells, previously shown to express CD38, were evaluated for immunosuppressive activity and Daratumumab sensitivity in the myeloma setting. A novel subpopulation of regulatory T cells (Tregs) expressing CD38 was identified. These Tregs were more immunosuppressive in vitro than CD38-negative Tregs and were reduced in daratumumab-treated patients. In parallel, daratumumab induced robust increases in helper and cytotoxic T-cell absolute counts. In PB and BM, daratumumab induced significant increases in CD8+:CD4+ and CD8+: Treg ratios, and increased memory T cells while decreasing naive T cells. The majority of patients demonstrated these broad T-cell changes, although patients with a partial response or better showed greater maximum effector and helper T-cell increases, elevated antiviral and alloreactive functional responses, and significantly greater increases in T-cell clonality as measured by T-cell receptor (TCR) sequencing. Increased TCR clonality positively correlated with increased CD8+ PBT-cell counts. Depletion of CD38+ immunosuppressive cells, which is associated with an increase in T-helper cells, cytotoxic T cells, T-cell functional response, and TCR clonality, represents possible additional mechanisms of action for daratumumab and deserves further exploration. (Blood. 2016;128(3):384-394)

Interesting points from the article (from kidney transplant perspective):

-Daratumumab has shown promising antimyeloma activity in 2 clinical studies (GEN501

and SIRIUS) in patients with relapsed and refractory MM, resulting in remarkable response rates that include stringent complete responses (sCRs) and prolonged clinical responses in heavily pretreated patients.

-CD38 is expressed on the following cells (in addition to the cells mentioned in the abstract): Natural killer cells, Monocytes and normal plasma cells

Comment:

My interest in Daratumumab stems from my interest in the management of antibody-mediated rejection (AMR) and the humoral arm of the immune response. Donor-specific antibodies (DSA) are a major obstacle to kidney transplantation, in addition, they are the main cause of chronic allograft failure. Elimination of these antibodies is very difficult due to the presence of long-lived plasma cells that are very resistant to available therapeutic options.

The efficacy of this drug that has been demonstrated in resistant MM, makes it a potential therapy in desensitization and in the treatment of AMR. Additional potential benefits in AMR for this drug are related to targeting monocytes and natural killer cells, which are thought to be the effector cells of non-complement mediated allograft injury (in addition to neutrophils).

One drawback is its depletion of some of the regulatory cells, leading to increase in helper, cytotoxic and memory Tcells, which can lead to rejection. However, the presence of other anti-rejection drugs on board in the transplant setting, may counterbalance/modulate this effect. Appropriate clinical trials need to be conducted, to evaluate the full therapeutic potential and safety of this drug in transplantation .

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