Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is associated with a remarkably poor prognosis and with no treatment consensus. The identification of relevant therapeutic targets is challenging. Here, we investigated the immune functions, antileukemia efficacy and safety of CD28/4-1BB CAR T cells targeting CD123 the interleukin (IL)-3 receptor alpha chain which is overexpressed on BPDCN. We demonstrated that both retroviral and lentiviral engineering CD28/4-1BB CD123 CAR T cells exhibit effector functions against BPDCN cells through CD123 antigen recognition and that they efficiently kill BPDCN cell lines and BPDCN-derived PDX cells. In vivo, CD28/4-1BB CD123 CAR T-cell therapy displayed strong efficacy by promoting a decrease of BPDCN blast burden. Furthermore we showed that T cells from BPDCN patient transduced with CD28/4-1BB CD123 CAR successfully eliminate autologous BPDCN blasts in vitro. Finally, we demonstrated in humanized mouse models that these effector CAR T cells exert low or no cytotoxicity against various subsets of normal cells with low CD123 expression, indicating a potentially low on-target/off-tumor toxicity effect. Collectively, our data support the further evaluation for clinical assessment of CD28/4-1BB CD123 CAR T cells in BPDCN neoplasm.
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Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of tumors of haematopoeitic and lymphoid tissues. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO classification of tumors of haematopoietic and lymphoid tissues. Revised 4th ed. Lyon: IARC; 2017. p. 98–106.
Simonyan D, Gagnon MP, Duchesne T, Roos-Weil A. Effects of a telehealth programme using mobile data transmission on primary healthcare utilisation among children in Bamako, Mali. J Telemed Telecare. 2013;19:302–6.
Pagano L, Valentini CG, Grammatico S, Pulsoni A. Blastic plasmacytoid dendritic cell neoplasm: diagnostic criteria and therapeutical approaches. Br J Haematol. 2016;174:188–202.
Kharfan-Dabaja MA, Lazarus HM, Nishihori T, Mahfouz RA, Hamadani M. Diagnostic and therapeutic advances in blastic plasmacytoid dendritic cell neoplasm: a focus on hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2013;19:1006–12.
Pemmaraju N, Lane AA, Sweet KL, Stein AS, Vasu S, Blum W, et al. Tagraxofusp in blastic plasmacytoid dendritic-cell neoplasm. N Engl J Med. 2019;380:1628–37.
Taussig DC, Pearce DJ, Simpson C, Rohatiner AZ, Lister TA, Kelly G, et al. Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia. Blood. 2005;106:4086–92.
Garnache-Ottou F, Feuillard J, Ferrand C, Biichle S, Trimoreau F, Seilles E, et al. Extended diagnostic criteria for plasmacytoid dendritic cell leukaemia. Br J Haematol. 2009;145:624–36.
Broughton SE, Dhagat U, Hercus TR, Nero TL, Grimbaldeston MA, Bonder CS, et al. The GM-CSF/IL-3/IL-5 cytokine receptor family: from ligand recognition to initiation of signaling. Immunol Rev. 2012;250:277–302.
Hara T, Miyajima A. Function and signal transduction mediated by the interleukin 3 receptor system in hematopoiesis. Stem Cells. 1996;14:605–18.
Testa U, Pelosi E, Frankel A. CD 123 is a membrane biomarker and a therapeutic target in hematologic malignancies. Biomark Res. 2014;2:4.
Ehninger A, Kramer M, Rollig C, Thiede C, Bornhauser M, von Bonin M, et al. Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia. Blood Cancer J. 2014;4:e218.
Vergez F, Green AS, Tamburini J, Sarry JE, Gaillard B, Cornillet-Lefebvre P, et al. High levels of CD34+CD38low/-CD123+ blasts are predictive of an adverse outcome in acute myeloid leukemia: a Groupe Ouest-Est des Leucemies Aigues et Maladies du Sang (GOELAMS) study. Haematologica. 2011;96:1792–8.
Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11.
Angelot-Delettre F, Roggy A, Frankel AE, Lamarthee B, Seilles E, Biichle S, et al. In vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to SL-401, an interleukin-3 receptor targeted biologic agent. Haematologica. 2015;100:223–30.
Frankel AE, Woo JH, Ahn C, Pemmaraju N, Medeiros BC, Carraway HE, et al. Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients. Blood. 2014;124:385–92.
Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368:1509–18.
Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33:540–9.
June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science. 2018;359:1361–5.
Mardiros A, Dos Santos C, McDonald T, Brown CE, Wang X, Budde LE, et al. T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia. Blood. 2013;122:3138–48.
Gill S, Tasian SK, Ruella M, Shestova O, Li Y, Porter DL, et al. Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor-modified T cells. Blood. 2014;123:2343–54.
Thokala R, Olivares S, Mi T, Maiti S, Deniger D, Huls H, et al. Redirecting specificity of T cells using the Sleeping Beauty system to express chimeric antigen receptors by mix-and-matching of VL and VH domains targeting CD123+ tumors. PloS ONE. 2016;11:e0159477.
Cummins KD, Gill S. Anti-CD123 chimeric antigen receptor T-cells (CART): an evolving treatment strategy for hematological malignancies, and a potential ace-in-the-hole against antigen-negative relapse. Leuk Lymphoma. 2018;59:1539–53.
Tettamanti S, Marin V, Pizzitola I, Magnani CF, Giordano Attianese GM, Cribioli E, et al. Targeting of acute myeloid leukaemia by cytokine-induced killer cells redirected with a novel CD123-specific chimeric antigen receptor. Br J Haematol. 2013;161:389–401.
Tasian SK, Kenderian SS, Shen F, Ruella M, Shestova O, Kozlowski M, et al. Optimized depletion of chimeric antigen receptor T cells in murine xenograft models of human acute myeloid leukemia. Blood. 2017;129:2395–407.
Cai T, Galetto R, Gouble A, Smith J, Cavazos A, Konoplev S, et al. Pre-clinical studies of anti-CD123 CAR-T cells for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN). Blood. 2016;128:4039.
Philippe L, Ceroi A, Bole-Richard E, Jenvrin A, Biichle S, Perrin S, et al. Bortezomib as a new therapeutic approach for blastic plasmacytoid dendritic cell neoplasm. Haematologica. 2017;102:1861–8.
Pagano L, Valentini CG, Pulsoni A, Fisogni S, Carluccio P, Mannelli F, et al. Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: an Italian multicenter study. Haematologica. 2013;98:239–46.
Wang J, Jensen M, Lin Y, Sui X, Chen E, Lindgren CG, et al. Optimizing adoptive polyclonal T cell immunotherapy of lymphomas, using a chimeric T cell receptor possessing CD28 and CD137 costimulatory domains. Hum Gene Ther. 2007;18:712–25.
Stoiber S, Cadilha BL, Benmebarek MR, Lesch S, Endres S, Kobold S. Limitations in the design of chimeric antigen receptors for cancer therapy. Cells. 2019;8:472.
Gomes-Silva D, Mukherjee M, Srinivasan M, Krenciute G, Dakhova O, Zheng Y, et al. Tonic 4-1BB costimulation in chimeric antigen receptors impedes T cell survival and is vector-dependent. Cell Rep. 2017;21:17–26.
Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5:177ra38.
Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385:517–28.
Park JH, Riviere I, Gonen M, Wang X, Senechal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378:449–59.
Kawalekar OU, O’Connor RS, Fraietta JA, Guo L, McGettigan SE, Posey AD Jr, et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity. 2016;44:712.
Feucht J, Sun J, Eyquem J, Ho YJ, Zhao Z, Leibold J, et al. Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency. Nat Med. 2019;25:82–8.
Drent E, Poels R, Ruiter R, van de Donk N, Zweegman S, Yuan H, et al. Combined CD28 and 4-1BB costimulation potentiates affinity-tuned chimeric antigen receptor-engineered T cells. Clin Cancer Res. 2019;25:4014–25.
Klebanoff CA, Gattinoni L, Torabi-Parizi P, Kerstann K, Cardones AR, Finkelstein SE, et al. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc Natl Acad Sci USA. 2005;102:9571–6.
Gattinoni L, Zhong XS, Palmer DC, Ji Y, Hinrichs CS, Yu Z, et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med. 2009;15:808–13.
Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, et al. A human memory T cell subset with stem cell-like properties. Nat Med. 2011;17:1290–7.
Li F, Sutherland MK, Yu C, Walter RB, Westendorf L, Valliere-Douglass J, et al. Characterization of SGN-CD123A, a potent CD123-directed antibody-drug conjugate for acute myeloid leukemia. Mol Cancer Ther. 2018;17:554–64.
Xie LH, Biondo M, Busfield SJ, Arruda A, Yang X, Vairo G, et al. CD123 target validation and preclinical evaluation of ADCC activity of anti-CD123 antibody CSL362 in combination with NKs from AML patients in remission. Blood Cancer J. 2017;7:e567.
Kovtun Y, Jones GE, Adams S, Harvey L, Audette CA, Wilhelm A, et al. A CD123-targeting antibody-drug conjugate, IMGN632, designed to eradicate AML while sparing normal bone marrow cells. Blood Adv. 2018;2:848–58.
Pizzitola I, Anjos-Afonso F, Rouault-Pierre K, Lassailly F, Tettamanti S, Spinelli O, et al. Chimeric antigen receptors against CD33/CD123 antigens efficiently target primary acute myeloid leukemia cells in vivo. Leukemia. 2014;28:1596–605.
Chu SY, Pong E, Chen H, Phung S, Chan EW, Endo NA, et al. Immunotherapy with long-lived anti-CD123 × anti-CD3 bispecific antibodies stimulates potent T cell-mediated killing of human AML cell lines and of CD123+ cells in monkeys: a potential therapy for acute myelogenous leukemia. Blood. 2014;124:2316.
Ruella M, Barrett DM, Kenderian SS, Shestova O, Hofmann TJ, Perazzelli J, et al. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J Clin Invest. 2016;126:3814–26.
Al-Hussaini M, Rettig MP, Ritchey JK, Karpova D, Uy GL, Eissenberg LG, et al. Targeting CD123 in acute myeloid leukemia using a T-cell-directed dual-affinity retargeting platform. Blood. 2016;127:122–31.
Togami K, Pastika T, Stephansky J, Ghandi M, Christie AL, Jones KL, et al. DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistance. J Clin Invest. 2019;129:5005–19.
Giavridis T, van der Stegen SJC, Eyquem J, Hamieh M, Piersigilli A, Sadelain MCAR. T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med. 2018;24:731–8.
Norelli M, Camisa B, Barbiera G, Falcone L, Purevdorj A, Genua M, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med. 2018;24:739–48.
Bonini C, Bondanza A, Perna SK, Kaneko S, Traversari C, Ciceri F, et al. The suicide gene therapy challenge: how to improve a successful gene therapy approach. Mol Ther. 2007;15:1248–52.
Warda W, Larosa F, Neto Da Rocha M, Trad R, Deconinck E, Fajloun Z, et al. CML hematopoietic stem cells expressing IL1RAP can be targeted by chimeric antigen receptor-engineered T cells. Cancer Res. 2019;79:663–75.
Zhou X, Di Stasi A, Tey SK, Krance RA, Martinez C, Leung KS, et al. Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene. Blood. 2014;123:3895–905.
The authors would like to thank the animal technicians for their expertise in animal care and management. We thank Franck Monnien and the Biobank BB-0033-00024 “Tumorothèque Régionale de Franche-Comté (TRFC)” for providing tissue samples, Diaclone for collaboration for antibodies production, and Stemline for SL-401 providing. This study was supported by Programme de Recherche Translationnelle INCa (PRTK N°PRT-K-15-175), by the MiMedI project funded by BPI France (Grant No. DOS0060162/00) and the European Union through the European Regional Development Fund of the Region Bourgogne-Franche-Comte (Grant No. FC0013440), by the Region Bourgogne-Franche-Comté (IVIS Lumina Series III bioimager to P.S. #2016-0196), by the National Cancer Institute (INCa) DM/FC/sl/RT07 grant to CR and the Association Laurette Fugain (12/09) to EM.
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Bôle-Richard, E., Fredon, M., Biichlé, S. et al. CD28/4-1BB CD123 CAR T cells in blastic plasmacytoid dendritic cell neoplasm. Leukemia 34, 3228–3241 (2020). https://doi.org/10.1038/s41375-020-0777-1
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