CAR T-cells targeting CD117 effectively eliminate mast cells in preclinical models of advanced systemic mastocytosis

CAR T-cells targeting CD117 effectively eliminate mast cells in preclinical models of advanced systemic mastocytosis

  • Hoermann G, Sotlar K, Jawhar M, Kristensen T, Bachelot G, Nedoszytko B, et al. Standards of genetic testing in the diagnosis and prognostication of systemic mastocytosis in 2022: recommendations of the EU-US cooperative group. J Allergy Clin Immunology: Pract. 2022;10:1953–63.

    Article 
    CAS 

    Google Scholar
     

  • Valent P, Akin C, Sperr WR, Horny H-P, Arock M, Metcalfe DD, et al. New insights into the pathogenesis of mastocytosis: emerging concepts in diagnosis and therapy. Annu Rev Pathol Mech Dis. 2023;18:361–86.

    Article 
    CAS 

    Google Scholar
     

  • Akin C, Arock M, Carter MC, George TI, Valent P. Mastocytosis. Nat Rev Dis Primers. 2025;11:30.

  • Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016;374:2530–41.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gotlib J, Reiter A, Radia DH, Deininger MW, George TI, Panse J, et al. Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial. Nat Med. 2021;27:2192–9.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • DeAngelo DJ, Radia DH, George TI, Robinson WA, Quiery AT, Drummond MW, et al. Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial. Nat Med. 2021;27:2183–91.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Reiter A, Schwaab J, DeAngelo DJ, Gotlib JR, Deininger MW, Pettit KM, et al. Efficacy and safety of avapritinib in previously treated patients with advanced systemic mastocytosis. Blood Adv. 2022;6:5750–62.

  • Reiter A, Gotlib J, Álvarez-Twose I, Radia DH, Lübke J, Bobbili PJ, et al. Efficacy of avapritinib versus best available therapy in the treatment of advanced systemic mastocytosis. Leukemia. 2022;36:2108–20.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Valent P, Akin C, Hartmann K, Alvarez-Twose I, Brockow K, Hermine O, et al. Guideline article – consensus based updated diagnostic criteria and classification of mast cell disorders: a consensus proposal. Hemasphere. 2021;5:e646.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Valent P, Akin C, Sperr WR, Escribano L, Arock M, Horny HP, et al. Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. Leuk Res. 2003;27:635–41.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lim KH, Tefferi A, Lasho TL, Finke C, Patnaik M, Butterfield JH, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009;113:5727–36.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Georgin-Lavialle S, Lhermitte L, Dubreuil P, Chandesris M-OO, Hermine O, Damaj G. Mast cell leukemia. Blood. 2013;121:1285–95.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Valent P, Akin C, Arock M, Gleixner KV, Greinix H, Hermine O, et al. Antibody-based and cell therapies for advanced mastocytosis: established and novel concepts. Int J Mol Sci. 2023;24:15125.

  • McLornan DP, Czerw T, Damaj G, Ethell M, Gurnari C, Hernández-Boluda JC, et al. Allogeneic haematopoietic cell transplantation for advanced systemic mastocytosis: Best practice recommendations on behalf of the EBMT Practice Harmonisation and Guidelines Committee. Leukemia. 2024;38:699–711.

  • Ustun C, Gotlib J, Popat U, Artz A, Litzow M, Reiter A, et al. Consensus opinion on allogeneic hematopoietic cell transplantation in advanced systemic mastocytosis. Biol Blood Marrow Transpl. 2016;22:1348–56.

    Article 

    Google Scholar
     

  • Ustun C, Reiter A, Scott BL, Nakamura R, Damaj G, Kreil S, et al. Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol. 2014;32:3264–74.

  • Valent P, Sperr WR, Akin C. How I treat patients with advanced systemic mastocytosis. Blood. 2010;116:5812–7.

  • Sriskandarajah P, McLornan DP, Oni C, Wilson AJ, Woodley C, Ciesielska M, et al. Advanced Systemic Mastocytosis with associated haematological neoplasm: Treatment with avapritinib can facilitate successful bridge to allogeneic haematopoietic cell transplant. Curr Res Transl Med. 2023;71:103398.

    CAS 
    PubMed 

    Google Scholar
     

  • Lübke J, Christen D, Schwaab J, Kaiser A, Naumann N, Shoumariyeh K, et al. Allogeneic hematopoietic cell transplantation in advanced systemic mastocytosis: a retrospective analysis of the DRST and GREM registries. Leukemia. 2024;38:810–21.

  • Brudno JN, Maus MV, Hinrichs CS. CAR T cells and T-cell therapies for cancer: a translational science review. JAMA. 2024;332:1924.

  • June CH, O’connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science (1979) 2018;359:1361–65.

  • Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531–44.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Berdeja JG, Madduri D, Usmani SZ, Jakubowiak A, Agha M, Cohen AD, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021;398:314–24.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Loff S, Dietrich J, Meyer JE, Riewaldt J, Spehr J, von Bonin M, et al. Rapidly switchable universal CAR-T cells for treatment of CD123-positive leukemia. Mol Ther Oncolytics. 2020;17:408–20.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xue T, Del Real M, Marcucci E, Toribio C, Setayesh SM, Forman SJ, et al. Checkpoint blockade in combination with CD33 chimeric antigen receptor T cell therapy and hypomethylating agent against acute myeloid leukemia. Blood. 2019;134:1383.

    Article 

    Google Scholar
     

  • Magnani CF, Myburgh R, Brunn S, Chambovey M, Ponzo M, Volta L, et al. Anti-CD117 CAR T cells incorporating a safety switch eradicate human acute myeloid leukemia and hematopoietic stem cells. Mol Ther Oncolytics. 2023;30:56–71.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Myburgh R, Kiefer JD, Russkamp NF, Magnani CF, Nuñez N, Simonis A, et al. Anti-human CD117 CAR T-cells efficiently eliminate healthy and malignant CD117-expressing hematopoietic cells. Leukemia. 2020;34:2688–703.

  • Volta L, Myburgh R, Hofstetter M, Koch C, Kiefer JD, Gobbi C, et al. A single-chain variable fragment-based bispecific T-cell activating antibody against CD117 enables T-cell mediated lysis of acute myeloid leukemia and hematopoietic stem and progenitor cells. HemaSphere. 2024;8:e70055.

  • Hoermann G, Blatt K, Greiner G, Putz EM, Berger A, Herrmann H, et al. CD52 is a molecular target in advanced systemic mastocytosis. FASEB J. 2014;28:3540–51.

  • Kirshenbaum AS, Yin Y, Bruce Sundstrom J, Bandara G, Metcalfe DD Description and characterization of a novel human mast cell line for scientific study. Int J Mol Sci 2019;20:5520.

  • Butterfield JH, Weiler D, Dewald G, Gleich GJ. Establishment of an immature mast cell line from a patient with mast cell leukemia. Leuk Res. 1988;12:345–55.

  • Saleh R, Wedeh G, Herrmann H, Bibi S, Cerny-Reiterer S, Sadovnik I, et al. A new human mast cell line expressing a functional IgE receptor converts to tumorigenic growth by KIT D816V transfection. Blood. 2014;124:111–20.

  • Toledo AMAS, Gatz M, Sontag S, Karoline V, Rossetti G, Sechi AS, et al. Nintedanib targets KIT D816V neoplastic cells derived from induced pluripotent stem cells of systemic mastocytosis. Blood. 2021;137:2070–84.

  • de Toledo MAS, Fu X, Maié T, Buhl EM, Götz K, Schmitz S, et al. KIT D816V mast cells derived from induced pluripotent stem cells recapitulate systemic mastocytosis transcriptional profile. Int J Mol Sci. 2023;24:5275.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rongvaux A, Willinger T, Martinek J, Strowig T, Gearty SV, Teichmann LL, et al. Development and function of human innate immune cells in a humanized mouse model. Nat Biotechnol. 2014;32:364–72.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Theocharides APAA, Rongvaux A, Fritsch K, Flavell RA, Manz MG. Humanized hemato-lymphoid system mice. Haematologica. 2016;101:5–19.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ellegast JM, Rauch PJ, Kovtonyuk LV, Müller R, Wagner U, Saito Y, et al. inv(16) and NPM1mut AMLs engraft human cytokine knock-in mice. Blood. 2016;128:2130–4.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Teodosio C, Mayado A, Sánchez-Muñoz L, Morgado JM, Jara-Acevedo M, Ivan´ Ivan´alvarez-Twose I, et al. The immunophenotype of mast cells and its utility in the diagnostic work-up of systemic mastocytosis. J Leukoc Biol. 2015;97:49–59.

  • Bonifant CL, Szoor A, Torres D, Joseph N, Velasquez MP, Iwahori K, et al. CD123-engager T cells as a novel immunotherapeutic for acute myeloid leukemia. Mol Ther. 2016;24:1615–26.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Boucher JC, Shrestha B, Vishwasrao P, Leick M, Cervantes EV, Ghafoor T, et al. Bispecific CD33/CD123 targeted chimeric antigen receptor T cells for the treatment of acute myeloid leukemia. Mol Ther Oncolytics. 2023;31:100751.

  • Volta L, Myburgh R, Pellegrino C, Koch C, Maurer M, Manfredi F, et al. Efficient combinatorial adaptor-mediated targeting of acute myeloid leukemia with CAR T-cells. Leukemia. 2024;38:2598–613.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bibi S, Zhang Y, Hugonin C, Mangean MD, He L, Wedeh G, et al. A new humanized in vivo model of KIT D816V+ advanced systemic mastocytosis monitored using a secreted luciferase. Oncotarget. 2016;7:82985–83000.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Eisenwort G, Sadovnik I, Schwaab J, Jawhar M, Keller A, Stefanzl G, et al. Identification of a leukemia-initiating stem cell in human mast cell leukemia. Leukemia. 2019;33:2673–84.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Blatt K, Cerny-Reiterer S, Schwaab J, Sotlar K, Eisenwort G, Stefanzl G, et al. Identification of the Ki-1 antigen (CD30) as a novel therapeutic target in systemic mastocytosis Key Points. Blood. 2015;126:2832–41.

  • Lysenko V, Van Wijk NWV, Zimmermann K, Weller MC, Bühler M, Wildschut MHE, et al. Enhanced engraftment of human myelofibrosis stem and progenitor cells in MISTRG mice. Blood Adv. 2020;4:2477–88.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Song Y, Rongvaux A, Taylor A, Jiang T, Tebaldi T, Balasubramanian K, et al. A highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies. Nat Commun. 2019;10:366.

  • Yu H, Borsotti C, Schickel J-N, Zhu S, Strowig T, Eynon EE, et al. A novel humanized mouse model with significant improvement of class-switched, antigen-specific antibody production Key Points. Blood. 2017;129:959–69.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Desai A, Jung MY, Olivera A, Gilfillan AM, Prussin C, Kirshenbaum AS, et al. IL-6 promotes an increase in human mast cell numbers and reactivity through suppression of suppressor of cytokine signaling 3. J Allergy Clin Immunol. 2016;137:1863–1871.e6.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Metcalfe DD, Baram D, Mekori YA. Mast cells. Physiol Rev. 1997;77:1033–79.

  • da Silva EZM, Jamur MC, Oliver C. Mast cell function: a new vision of an old cell. J Histochem Cytochem. 2014;62:698–738.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Broesby-Olsen S, Vestergaard H, Mortz CG, Jensen B, Havelund T, Hermann AP, et al. Omalizumab prevents anaphylaxis and improves symptoms in systemic mastocytosis: Efficacy and safety observations. Allergy. 2018;73:230–8.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Krauth MT, Böhm A, Agis H, Sonneck K, Samorapoompichit P, Florian S, et al. Effects of the CD33-targeted drug gemtuzumab ozogamicin (Mylotarg) on growth and mediator secretion in human mast cells and blood basophils. Exp Hematol. 2007;35:108–16.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Alvarez-Twose I, Martínez-Barranco P, Gotlib J, García-Montero A, Morgado JM, Jara-Acevedo M, et al. Complete response to gemtuzumab ozogamicin in a patient with refractory mast cell leukemia. Leukemia. 2016;30:1753–6.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gotlib J, Baird JH, George TI, Langford C, Reyes I, Abuel J, et al. A phase 2 study of brentuximab vedotin in patients with CD30-positive advanced systemic mastocytosis. Blood Adv. 2019;3:2264–71.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Russkamp NF, Myburgh R, Kiefer JD, Neri D, Manz MG. Anti-CD117 immunotherapy to eliminate hematopoietic and leukemia stem cells. Exp Hematol. 2021;95:31–45.

  • Manz MG, Russkamp NF. Selective CD117 + HSC exchange therapy. Blood. 2019;133:2007–9.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pang WW, Czechowicz A, Logan AC, Bhardwaj R, Poyser J, Park CY, et al. Anti-CD117 antibody depletes normal and myelodysplastic syndrome human hematopoietic stem cells in xenografted mice. Blood. 2019;133:2069–78.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Agarwal R, Bertaina A, Soco C, Long-Boyle JR, Saini G, Kunte N, et al. Irradiation- and busulfan-free stem cell transplantation in Fanconi anemia using an anti-CD117 antibody: a phase 1b trial. Nat Med. 2025;31:3183–90.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Thomas R, Ritchey JK, DiPersio JF, Kim MY. Targeting CD117 on hematopoietic stem and progenitor cells impairs CAR T cell activity. Mol Ther. 2025;33:4584–99.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar