CD34 + CD19 − CD22 + B-cell progenitors may underlie phenotypic escape in patients treated with CD19-directed therapies
Bueno, Clara (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Barrera, Susana (Universidad de Salamanca)
Bataller, Alex (Hospital Clínic i Provincial de Barcelona)
Ortiz-Maldonado, Valentín (Hospital Clínic i Provincial de Barcelona)
Elliot, Natalina (John Radcliffe Hospital (Oxford, Regne Unit))
O'Byrne, Sorcha (John Radcliffe Hospital (Oxford, Regne Unit))
Wang, Guanlin (University of Oxford)
Rovira, Montse (University of Oxford)
Gutiérrez-Agüera, Francisco (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Trincado Alonso, Juan Luis, 1987- (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
González-González, María (Universidad de Salamanca)
Morgades, Mireia (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Sorigue, Marc (Universitat Autònoma de Barcelona)
Bárcena, Paloma (Universidad de Salamanca)
Zanetti, S. R (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Torrebadell, Montse (Hospital Sant Joan de Déu (Barcelona, Catalunya))
Vega-Garcia, Nerea (Hospital Sant Joan de Déu (Barcelona, Catalunya))
Rives, Susana (Hospital Sant Joan de Déu (Barcelona, Catalunya))
Mallo, Maria del Mar (Universitat Autònoma de Barcelona)
Sole, F (Universitat Autònoma de Barcelona)
Mead, Adam J. (Centro Nacional de Investigaciones Oncológicas Carlos III (Espanya))
Roberts, Irene (Oxford Biomedical Research Centre)
Thongjuea, Supat (Hospital Sant Joan de Déu (Barcelona, Catalunya))
Psaila, Bethan (Oxford Biomedical Research Centre)
Juan, Manel (Hospital Clínic i Provincial de Barcelona)
Delgado, Julio (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Urbano-Ispizúa, Alvaro (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Ribera, Jose-Maria (Universitat Autònoma de Barcelona)
Orfao, Alberto (Universidad de Salamanca)
Roy, Anindita (Oxford Biomedical Research Centre)
Menéndez Bujan, Pablo (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)

Fecha:	2022
Resumen:	Three article in this issue present preclinical data aimed at improving immunotherapeutic approaches for relapsed B- and T-cell acute lymphoblastic leukemia (T-ALL). Chimeric antigen receptor T (CAR-T) cell therapy directed against relapsed T-ALL is hampered by difficulty in identifying a target antigen that is not also expressed on healthy T cells, risking "fratricide" with T-cell aplasia and loss of the CAR-T cells. Maciocia and colleagues identify CCR9 as an antigen expressed on >85% of relapsed T-ALL and on <5% of normal T cells, demonstrating in cell lines and patient-derived xenografts that CAR-T cells targeting CCR9 have potent anti-leukemic activity without any evidence of fratricide. In the second article, Müller et al explore the potential of dual antibody targeting of CD47 and CD38 in a preclinical models of T-ALL; although CD47 does not avoid the risk of aplasia, it shows efficacy in combination with daratumumab in treating relapsed T-ALL and eradicating MRD. Finally, the third article addresses relapse following CD19-directed immunotherapies for B-ALL, which may be mediated by recurrence of CD19-negative leukemia. Bueno et al identify CD34 + CD19 − CD22 + cells in patients at diagnosis and relapse; they further show that CD22 expression precedes CD19 expression and that this population harbors the same genetic abnormalities of the B-ALL clone. They propose that this may represent a progenitor population that can give rise to B-ALL recurrence, supporting the use of combined CAR-T therapies, perhaps directed at both CD19 and CD22. CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphoblastic leukemia (B-ALL). Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. Patients with B-ALL successfully treated with CD19-directed T cells eventually relapse, which, coupled with the early onset of CD22 expression during B-cell development, suggests that preexisting CD34 + CD22 + CD19 − (pre)-leukemic cells represent an "early progenitor origin-related" mechanism underlying phenotypic escape to CD19-directed immunotherapies. We demonstrate that CD22 expression precedes CD19 expression during B-cell development. CD34 + CD19 − CD22 + cells are found in diagnostic and relapsed bone marrow samples of ∼70% of patients with B-ALL, and their frequency increases twofold in patients with B-ALL in CR after CD19 CAR T-cell therapy. The median of CD34 + CD19 − CD22 + cells before treatment was threefold higher in patients in whom B-ALL relapsed after CD19-directed immunotherapy (median follow-up, 24 months). Fluorescence in situ hybridization analysis in flow-sorted cell populations and xenograft modeling revealed that CD34 + CD19 − CD22 + cells harbor the genetic abnormalities present at diagnosis and initiate leukemogenesis in vivo. Our data suggest that preleukemic CD34 + CD19 − CD22 + progenitors underlie phenotypic escape after CD19-directed immunotherapies and reinforce ongoing clinical studies aimed at CD19/CD22 dual targeting as a strategy for reducing CD19 − relapses. The implementation of CD34/CD19/CD22 immunophenotyping in clinical laboratories for initial diagnosis and subsequent monitoring of patients with B-ALL during CD19-targeted therapy is encouraged.
Ayudas:	Agencia Estatal de Investigación PID2019-108160RB-I00 Instituto de Salud Carlos III PI17/01028 Instituto de Salud Carlos III PI20/00822
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Publicado en:	Blood, Vol. 140 (july 2022) , p. 38-44, ISSN 1528-0020

DOI: 10.1182/blood.2021014840
PMID: 35421218

14 p, 1.0 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Instituto de Investigación contra la Leucemia Josep Carreras
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