[en] Multiple myeloma (MM) is an incurable cancer characterized by the proliferation and accumulation of monoclonal plasma cells in the bone marrow. The monoclonal anti-CD38 daratumumab has taken a central place in the different treatment regimens for newly diagnosed and relapsed, refractory myeloma. In this study, we correlated the NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and potential fratricide induced by daratumumab with CD38-expression levels on both effector and target cells. We show that CD38 expression can be modulated by adding all-trans retinoic acid (ATRA) or interferon-α to MM cells to further fine-tune these effects. In addition, we observed that ADCC becomes inefficient when fratricide occurs and both ADCC and fratricide depend on the balance between CD38 expression on effector and target cells. However, the addition of adjuvants (retinoic acid or interferon-α) to myeloma cells or the inhibition of fratricide using a CD38-blocking nanobody on NK-cells can reverse this balance towards ADCC and thus promote lysis of target cells by ADCC. ATRA and interferon-α increased the CD38 expression at the surface of MM cells about three-fold and two-fold, respectively. This increase was of interest for MM cells with low CD38 expression, that became susceptible to daratumumab-mediated ADCC after preincubation. A CD38-blocking nanobody prevented the binding of daratumumab to these NK-cells and blunted the fratricidal effect on effector NK cells. In conclusion, our study highlights the importance of a balanced CD38 expression on target and effector cells and attempts to alter this balance will affect the susceptibility of MM cells towards daratumumab-mediated ADCC.
Cho, S.-F.; Lin, L.; Xing, L.; Yu, T.; Wen, K.; Anderson, K.C.; Tai, Y.-T. Monoclonal Antibody: A New Treatment Strategy against Multiple Myeloma. Antibodies 2017;6(4):18, doi:10.3390/antib6040018
Abramson, H.N. Monoclonal Antibodies for the Treatment of Multiple Myeloma: An Update. Int. J. Mol. Sci. 201819(12):3924. doi:10.3390/ijms19123924
Fast, L.D.; Hansen, J.A.; Newman, W. Evidence for T cell nature and heterogeneity within natural killer (NK) and antibody-dependent cellular cytotoxicity (ADCC) effectors: A comparison with cytolytic T lymphocytes (CTL). J. Immunol. 1981, 127, 448– 452.
Mahaweni, N.M.; Bos, G.M.J.; Mitsiades, C.S.; Tilanus, M.G.J.; Wieten, L. Daratumumab augments alloreactive natural killer cell cytotoxicity towards CD38+ multiple myeloma cell lines in a biochemical context mimicking tumour microenvironment conditions. Cancer Immunol. Immunother. 2018, 67, 861–872, doi:10.1007/s00262-018-2140-1.
Deaglio, S.; Mehta, K.; Malavasi, F. Human CD38: A (r)evolutionary story of enzymes and receptors. Leuk. Res. 2001, 25, 1–12, doi:10.1016/s0145-2126(00)00093-x.
Lokhorst, H.M.; Plesner, T.; Laubach, J.P.; Nahi, H.; Gimsing, P.; Hansson, M.; Minnema, M.C.; Lassen, U.; Krejcik, J.; Palumbo, A.; et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N. Engl. J. Med. 2015, 373, 1207–1219, doi:10.1056/nejmoa1506348.
Bahlis, N.J.; Dimopoulos, M.A.; White, D.J.; Benboubker, L.; Cook, G.; Leiba, M.; Ho, P.J.; Kim, K.; Takezako, N.; Moreau, P.; et al. Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: Extended follow-up of POLLUX, a randomized, open-label, phase 3 study. Leukemia 2020, 34, 1875–1884, doi:10.1038/s41375-020-0711-6.
Palumbo, A.; Chanan-Khan, A.; Weisel, K.; Nooka, A.K.; Masszi, T.; Beksac, M.; Spicka, I.; Hungria, V.; Munder, M.; Mateos, M.V.; et al. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N. Engl. J. Med. 2016, 375, 754–766, doi:10.1056/nejmoa1606038.
Dimopoulos, M.; Oriol, A.; Nahi, H.; San-Miguel, J.; Bahlis, N.J.; Usmani, S.Z.; Rabin, N.; Orlowski, R.; Komarnicki, M.; Suzuki, K.; et al. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N. Engl. J. Med. 2016, 375, 1319–1331, doi:10.1056/nejmoa1607751.
Nijhof, I.S.; Casneuf, T.; Van Velzen, J.; Van Kessel, B.; Axel, A.E.; Syed, K.; Groen, R.W.J.; Van Duin, M.; Sonneveld, P.; Minnema, M.C.; et al. CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma. Blood 2016, 128, 959–970, doi:10.1182/blood-2016-03-703439.
Casneuf, T.; Xu, X.S.; Adams, H.C.; Axel, A.E.; Chiu, C.; Khan, I.; Ahmadi, T.; Yan, X.; Lonial, S.; Plesner, T.; et al. Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma. Blood Adv. 2017, 1, 2105–2114, doi:10.1182/bloodadvances.2017006866.
Wang, Y.; Zhang, Y.; Hughes, T.; Zhang, J.; Caligiuri, M.A.; Benson, D.M.; Yu, J. Fratricide of NK Cells in Daratumumab Therapy for Multiple Myeloma Overcome by Ex Vivo–Expanded Autologous NK Cells. Clin. Cancer Res. 2018, 24, 4006–4017, doi:10.1158/1078-0432.ccr-17-3117.
Tonn, T.; Schwabe, D.; Klingemann, H.G.; Becker, S.; Esser, R.; Koehl, U.; Suttorp, M.; Seifried, E.; Ottmann, O.; Bug, G. Treatment of patients with advanced cancer with the natural killer cell line NK-92. Cytotherapy 2013, 15, 1563–1570, doi:10.1016/j.jcyt.2013.06.017.
Arai, S.; Meagher, R.; Swearingen, M.; Myint, H.; Rich, E.; Martinson, J.; Klingemann, H. Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: A phase I trial. Cytotherapy 2008, 10, 625–632, doi:10.1080/14653240802301872.
Williams, B.A.; Law, A.D.; Routy, B.; Denhollander, N.; Gupta, V.; Wang, X.-H.; Chaboureau, A.; Viswanathan, S.; Keating, A. A phase I trial of NK-92 cells for refractory hematological malignancies relapsing after autologous hematopoietic cell transplantation shows safety and evidence of efficacy. Oncotarget 2017, 8, 89256–89268, doi:10.18632/oncotarget.19204.
Clémenceau, B.; Vivien, R.; Pellat, C.; Foss, M.; Thibault, G.; Vié, H. The human natural killer cytotoxic cell line NK-92, once armed with a murine CD16 receptor, represents a convenient cellular tool for the screening of mouse mAbs according to their ADCC potential. MAbs 2013, 5, 587–594, doi:10.4161/mabs.25077.
Emi, N.; Friedmann, T.; Yee, J.K. Pseudotype formation of murine leukemia virus with the G protein of vesicular stomatitis virus. J. Virol. 1991, 65, 1202–1207, doi:10.1128/jvi.65.3.1202-1207.1991.
Li, T.; Qi, S.; Unger, M.; Hou, Y.N.; Deng, Q.W.; Liu, J.; Lam, C.M.C.; Wang, X.W.; Xin, D.; Zhang, P.; et al. Immuno-targeting the multifunctional CD38 using nanobody. Sci. Rep. 2016, 6, 27055, doi:10.1038/srep27055.
Nijhof, I.S.; Groen, R.W.J.; Lokhorst, H.M.; Van Kessel, B.; Bloem, A.C.; Van Velzen, J.; De Jong-Korlaar, R.; Yuan, H.; Noort, W.A.; Klein, S.K.; et al. Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab. Leukemia 2015, 29, 2039–2049, doi:10.1038/leu.2015.123.
Heidenreich, S.; Eulenburg, C.Z.; Hildebrandt, Y.; Stubig, T.; Sierich, H.; Badbaran, A.; Eiermann, T.H.; Binder, T.M.C.; Kroger, N. Impact of the NK cell receptor LIR-1 (ILT-2/CD85j/LILRB1) on cytotoxicity against multiple myeloma. Clin. Dev. Immunol. 2012, 2012, 652130.
Kararoudi, M.N.; Nagai, Y.; Elmas, E.; Pereira, M.D.S.F.; Ali, S.A.; Imus, P.H.; Wethington, D.; Borrello, I.M.; Lee, D.A.; Ghiaur, G. CD38 deletion of human primary NK cells eliminates daratumumab-induced fratricide and boosts their effector activity. Blood 2020, 136, 2416–2427, doi:10.1182/blood.2020006200.
Sarkar, S.; Chauhan, S.K.S.; Daly, J.; Natoni, A.; Fairfield, H.; Henderson, R.; Nolan, E.; Swan, D.; Hu, J.; Reagan, M.R.; et al. The CD38low natural killer cell line KHYG1 transiently expressing CD16F158V in combination with daratumumab targets multiple myeloma cells with minimal effector NK cell fratricide. Cancer Immunol. Immunother. 2020, 69, 421–434, doi:10.1007/s00262-019-02477-8.
Lewandowski, D.; Linassier, C.; Iochmann, S.; Degenne, M.; Domenech, J.; Colombat, P.; Binet, C.; Herault, O. Phosphatidylino-sitol 3-kinases are involved in the all-trans retinoic acid-induced upregulation of CD38 antigen on human haematopoietic cells. Br. J. Haematol. 2002, 118, 535–544.
Mihara, K.; Yoshida, T.; Ishida, S.; Takei, Y.; Kitanaka, A.; Shimoda, K.; Morishita, K.; Takihara, Y.; Ichinohe, T. All-trans retinoic acid and interferon-α increase CD38 expression on adult T-cell leukemia cells and sensitize them to T cells bearing anti-CD38 chimeric antigen receptors. Blood Cancer J. 2016, 6, e421, doi:10.1038/bcj.2016.30.
García-Guerrero, E.; Götz, R.; Doose, S.; Sauer, M.; Rodríguez-Gil, A.; Nerreter, T.; Kortüm, K.M.; Pérez-Simón, J.A.; Einsele, H.; Hudecek, M.; et al. Upregulation of CD38 expression on multiple myeloma cells by novel HDAC6 inhibitors is a class effect and augments the efficacy of daratumumab. Leukemia 2021, 35, 201–214, doi:10.1038/s41375-020-0840-y.
Fatholahi, M.; Valencia, M.; Mark, A.; Bi, M.; Syed, S.; Zhang, Y.; Taura, T.; Yun, Y.; Wilson, D.; Chattopadhyay, N.; et al. TAK-573, an anti-CD38-targeted attenuated interferon alpha (IFNα) fusion protein, showed anti-myeloma tumor responses in combination with standard of care (SOC) agents in multiple myeloma (MM) xenograft tumor models in vivo. Clin. Lymphoma Myeloma Leuk. 2019, 19, e116, doi:10.1016/j.clml.2019.09.192.
Capuano, C.; Pighi, C.; Battella, S.; De Federicis, D.; Galandrini, R.; Palmieri, G. Harnessing CD16-Mediated NK Cell Functions to Enhance Therapeutic Efficacy of Tumor-Targeting mAbs. Cancers 2021;13(10):2500, doi:10.3390/cancers13102500.
Motais, B.; Charvátová, S.; Walek, Z.; Hrdinka, M.; Smolarczyk, R.; Cichoń, T.; Czapla, J.; Giebel, S.; Šimíček, M.; Jelínek, T.; et al. Selection, Expansion, and Unique Pretreatment of Allogeneic Human Natural Killer Cells with Anti-CD38 Monoclonal Antibody for Efficient Multiple Myeloma Treatment. Cells 2021 10(5):967 doi:10.3390/cells10050967.
Reina-Ortiz, C.; Constantinides, M.; Fayd-Herbe-De-Maudave, A.; Présumey, J.; Hernandez, J.; Cartron, G.; Giraldos, D.; Díez, R.; Izquierdo, I.; Azaceta, G.; et al. Expanded NK cells from umbilical cord blood and adult peripheral blood combined with daratumumab are effective against tumor cells from multiple myeloma patients. OncoImmunology 2020, 10, 1853314, doi:10.1080/2162402x.2020.1853314.
Adams, H.C., 3rd; Stevenaert, F.; Krejcik, J.; van der Borght, K.; Smets, T.; Bald, J.; Abraham, Y.; Ceulemans, H.; Chiu, C.; Vanhoof, G.; et al. High-Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action. Cytometry A 2019, 95, 279–289.
Krejcik, J.; Casneuf, T.; Nijhof, I.S.; Verbist, B.; Bald, J.; Plesner, T.; Syed, K.; Liu, K.; Van De Donk, N.W.C.J.; Weiss, B.M.; et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood 2016, 128, 384–394, doi:10.1182/blood-2015-12-687749.