CAR T-cells targeting FLT3 have potent activity against FLT3−ITD+ AML and act synergistically with the FLT3-inhibitor crenolanib (original) (raw)

References

  1. Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002;100:1532–42.
    Article CAS Google Scholar
  2. Kikushige Y, Yoshimoto G, Miyamoto T, Iino T, Mori Y, Iwasaki H, et al. Human Flt3 is expressed at the hematopoietic stem cell and the granulocyte/macrophage progenitor stages to maintain cell survival. J Immunol. 2008;180:7358–67.
    Article CAS Google Scholar
  3. Böiers C, Buza-Vidas N, Jensen CT, Pronk CJ, Kharazi S, Wittmann L, et al. Expression and role of FLT3 in regulation of the earliest stage of normal granulocyte-monocyte progenitor development. Blood. 2010;115:5061–8.
    Article Google Scholar
  4. Rosnet O, Bühring H, Marchetto S, Rappold I, Lavagna C, Sainty D, et al. Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia. 1996;10:238–48.
    CAS PubMed Google Scholar
  5. Karsunky H, Merad M, Cozzio A, Weissman IL, Manz MG. Flt3 ligand regulates dendritic cell development from Flt3+lymphoid and myeloid-committed progenitors to Flt3+dendritic cells in vivo. J Exp Med. 2003;198:305–13.
    Article CAS Google Scholar
  6. Park I-K, Trotta R, Yu J, Caligiuri MA. Axl/Gas6 pathway participates in human natural killer cell development by positively regulating FLT3 activation. Eur J Immunol 2013;43:2750–5.
  7. Waskow C, Liu K, Darrasse-Jèze G, Guermonprez P, Ginhoux F, Merad M, et al. The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral lymphoid tissues. Nat Immunol. 2008;9:676–83.
    Article CAS Google Scholar
  8. Carow CE, Levenstein M, Kaufmann SH, Chen J, Amin S, Rockwell P, et al. Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood. 1996;87:1089–96.
    CAS PubMed Google Scholar
  9. Ozeki K, Kiyoi H, Hirose Y, Iwai M, Ninomiya M, Kodera Y, et al. Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. Blood. 2004;103:1901–8.
    Article CAS Google Scholar
  10. Vora HH, Shukla SN, Brahambhatt BV, Mehta SH, Patel NA, Parikh SK, et al. Clinical relevance of FLT3 receptor protein expression in Indian patients with acute leukemia. Asia‐Pacific J Clin Oncol. 2010;6:306–19.
    Article Google Scholar
  11. Kindler T, Lipka DB, Fischer T. FLT3 as a therapeutic target in AML: still challenging after all these years. Blood. 2010;116:5089–102.
    Article CAS Google Scholar
  12. Hofmann M, Große-Hovest L, Nübling T, Pyż E, Bamberg M, Aulwurm S, et al. Generation, selection and preclinical characterization of an Fc-optimized FLT3 antibody for the treatment of myeloid leukemia. Leukemia. 2012;26:1228–37.
    Article CAS Google Scholar
  13. Stone JD, Aggen DH, Schietinger A, Schreiber H, Kranz DM. A sensitivity scale for targeting T cells with chimeric antigen receptors (CARs) and bispecific T-cell Engagers (BiTEs). Oncoimmunology. 2012;1:863–73.
    Article Google Scholar
  14. Kuchenbauer F, Kern W, Schoch C, Kohlmann A, Hiddemann W, Haferlach T, et al. Detailed analysis of FLT3 expression levels in acute myeloid leukemia. Haematologica. 2005;90:1617–25.
    CAS PubMed Google Scholar
  15. Thiede C, Steudel C, Mohr B, Schaich M, Schäkel U, Platzbecker U, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99:4326–35.
    Article CAS Google Scholar
  16. Fröhling S, Scholl C, Levine RL, Loriaux M, Boggon TJ, Bernard OA, et al. Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles. Cancer Cell. 2007;12:501–13.
    Article Google Scholar
  17. Levis M, Murphy KM, Pham R, Kim K-T, Stine A, Li L, et al. Internal tandem duplications of the FLT3 gene are present in leukemia stem cells. Blood. 2005;106:673–80.
    Article CAS Google Scholar
  18. Brunet S, Labopin M, Esteve J, Cornelissen J, Socié G, Iori AP, et al. Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retrospective analysis. J Clin Oncol. 2012;30:735–41.
    Article Google Scholar
  19. Schmid C, Labopin M, Socié G, Daguindau E, Volin L, Huynh A, et al. Outcome of patients with distinct molecular genotypes and cytogenetically normal AML after allogeneic transplantation. Blood. 2015;126:2062–9.
    Article CAS Google Scholar
  20. Alvarado Y, Kantarjian HM, Luthra R, Ravandi F, Borthakur G, Garcia‐Manero G, et al. Treatment with FLT3 inhibitor in patients with FLT3‐mutated acute myeloid leukemia is associated with development of secondary FLT3–tyrosine kinase domain mutations. Cancer. 2014;120:2142–9.
    Article CAS Google Scholar
  21. Heidel F, Solem FK, Breitenbuecher F, Lipka DB, Kasper S, Thiede M, et al. Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain. Blood. 2006;107:293–300.
    Article CAS Google Scholar
  22. Knapper S, Burnett AK, Littlewood T, Kell WJ, Agrawal S, Chopra R, et al. A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood. 2006;108:3262–70.
    Article CAS Google Scholar
  23. Weisberg E, Ray A, Nelson E, Adamia S, Barrett R, Sattler M, et al. Reversible resistance induced by FLT3 inhibition: a novel resistance mechanism in mutant FLT3-expressing cells. PloS One. 2011;6:e25351.
    Article CAS Google Scholar
  24. Smith CC, Lasater EA, Lin KC, Wang Q, McCreery MQ, Stewart WK, et al. Crenolanib is a selective type I pan-FLT3 inhibitor. Proc Natl Acad Sci. 2014;111:5319–24.
    Article CAS Google Scholar
  25. Zimmerman EI, Turner DC, Buaboonnam J, Hu S, Orwick S, Roberts MS, et al. Crenolanib is active against models of drug-resistant FLT3-ITD− positive acute myeloid leukemia. Blood. 2013;122:3607–15.
    Article CAS Google Scholar
  26. Heinrich MC, Griffith D, McKinley A, Patterson J, Presnell A, Ramachandran A, et al. Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors. Clin Cancer Res. 2012;18:4375–84.
    Article CAS Google Scholar
  27. Wetmore C, Broniscer A, Turner D, Wright KD, Pai-Panandiker A, Kun LE. et al. First-in-pediatrics phase I study of crenolanib besylate (CP-868,596-26) administered during and after radiation therapy (RT) in newly diagnosed diffuse intrinsic pontine glioma (DIPG) and recurrent high-grade glioma (HGG). J Clin Oncol. 2014;32:10064
    Article Google Scholar
  28. Randhawa JK, Kantarjian HM, Borthakur G, Thompson PA, Konopleva M, Daver N. et al. Results of a phase II study of crenolanib in relapsed/refractory acute myeloid leukemia patients (Pts) with activating FLT3 mutations. Blood. 2014;124:389
    Google Scholar
  29. Cortes J. Results from a phase II study of crenolanib in patients with FLT3-positive acute myeloidleukemia. ASCO Annual Meeting Chicago, IL, USA. 2016.
  30. Hudecek M, Sommermeyer D, Kosasih PL, Silva-Benedict A, Liu L, Rader C, et al. The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity. Cancer Immunol Res. 2015;3:125–35.
    Article CAS Google Scholar
  31. Hudecek M, Lupo-Stanghellini M-T, Kosasih PL, Sommermeyer D, Jensen MC, Rader C, et al. Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T cells. Clin Cancer Res. 2013;19:3153–64.
    Article CAS Google Scholar
  32. Wang X, Chang W-C, Wong CW, Colcher D, Sherman M, Ostberg JR, et al. A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells. Blood. 2011;118:1255–63.
    Article CAS Google Scholar
  33. Monjezi R, Miskey C, Gogishvili T, Schleef M, Schmeer M, Einsele H, et al. Enhanced CAR T-cell engineering using non-viral Sleeping Beauty transposition from minicircle vectors. Leukemia. 2017;31:186–94.
    Article CAS Google Scholar
  34. 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.
    Article CAS Google Scholar
  35. Quentmeier H, Reinhardt J, Zaborski M, Drexler H. FLT3 mutations in acute myeloid leukemia cell lines. Leukemia. 2003;17:120.
    Article CAS Google Scholar
  36. Sanchez PV, Perry RL, Sarry JE, Perl AE, Murphy K, Swider CR, et al. A robust xenotransplantation model for acute myeloid leukemia. Leukemia. 2009;23:2109.
    Article CAS Google Scholar
  37. Galanis A, Ma H, Rajkhowa T, Ramachandran A, Small D, Cortes J, et al. Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Blood. 2014;123:94–100.
    Article CAS Google Scholar
  38. Chen J, Schmitt A, Chen B, Rojewski M, Rubeler V, Fei F, et al. Nilotinib hampers the proliferation and function of CD8+T lymphocytes through inhibition of T cell receptor signalling. J Cell Mol Med. 2008;12:2107–18.
    Article CAS Google Scholar
  39. Fei F, Yu Y, Schmitt A, Rojewski MT, Chen B, Greiner J, et al. Dasatinib exerts an immunosuppressive effect on CD8+T cells specific for viral and leukemia antigens. Exp Hematol. 2008;36:1297–308.
    Article CAS Google Scholar
  40. 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.
    Article CAS Google Scholar
  41. Turtle CJ, Hanafi L-A, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR–T cells of defined CD4+: CD8+composition in adult B cell ALL patients. J Clin Invest. 2016;126:2123–38.
    Article Google Scholar
  42. Paszkiewicz PJ, Fräßle SP, Srivastava S, Sommermeyer D, Hudecek M, Drexler I, et al. Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia. J Clin Invest. 2016;126:4262.
    Article Google Scholar
  43. Diaconu I, Ballard B, Zhang M, Chen Y, West J, Dotti G, et al. Inducible caspase-9 selectively modulates the toxicities of CD19-specific chimeric antigen receptor-modified T cells. Mol Ther. 2017;25:580–92.
    Article CAS Google Scholar
  44. 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.
    Article CAS Google Scholar
  45. Chen L, Mao H, Zhang J, Chu J, Devine S, Caligiuri M et al. Targeting FLT3 by chimeric antigen receptor T cells for the treatment of acute myeloid leukemia. Leukemia 2017;3:1830–4.
  46. Kenderian S, Ruella M, Shestova O, Klichinsky M, Aikawa V, Morrissette J, et al. CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. Leukemia. 2015;29:1637–47.
    Article CAS Google Scholar
  47. Gardner R, Wu D, Cherian S, Fang M, Hanafi L-A, Finney O, et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood. 2016;127:2406–10.
    Article CAS Google Scholar
  48. Sotillo E, Barrett DM, Black KL, Bagashev A, Oldridge D, Wu G, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 2015;5:1282–95.
    Article CAS Google Scholar
  49. 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.
    Article Google Scholar
  50. Shultz LD, Goodwin N, Ishikawa F, Hosur V, Lyons BL, Greiner DL. Human cancer growth and therapy in immunodeficient mouse models. Cold Spring Harb Protoc. 2014;2014:pdb. top073585.
    Article Google Scholar
  51. Pfister O, Lorenz V, Oikonomopoulos A, Xu L, Häuselmann SP, Mbah C, et al. FLT3 activation improves post-myocardial infarction remodeling involving a cytoprotective effect on cardiomyocytes. J Am Coll Cardiol. 2014;63:1011–9. 2014/03/18/
    Article CAS Google Scholar
  52. Feldman EJ, Brandwein J, Stone R, Kalaycio M, Moore J, O’connor J, et al. Phase III randomized multicenter study of a humanized anti-CD33 monoclonal antibody, lintuzumab, in combination with chemotherapy, versus chemotherapy alone in patients with refractory or first-relapsed acute myeloid leukemia. J Clin Oncol. 2005;23:4110–6.
    Article CAS Google Scholar
  53. Roberts A, He S, Ritchie D, Hertzberg M, Kerridge I, Durrant S. et al. A phase I study of anti-CD123 monoclonal antibody (mAb) CSL360 targeting leukemia stem cells (LSC) in AML. J Clin Oncol. 2010;28:e13012
    Article Google Scholar

Download references