title: Patient-individualized CD8⁺ cytolytic T-cell therapy effectively combats minimal residual leukemia in immunodeficient mice.
abstract: Adoptive transfer of donor-derived cytolytic T-lymphocytes (CTL) has evolved as a promising strategy to improve graft-versus-leukemia (GvL) effects in allogeneic hematopoietic stem-cell transplantation. However, durable clinical responses are often hampered by limited capability of transferred T cells to establish effective and sustained antitumor immunity in vivo. We therefore analyzed GvL responses of acute myeloid leukemia (AML)-reactive CD8(+) CTL with central and effector memory phenotype in a new allogeneic donor-patient specific humanized mouse model. CTL lines and clones obtained upon stimulation of naive CD45RA(+) donor CD8(+) T cells with either single HLA antigen-mismatched or HLA-matched primary AML blasts, respectively, elicited strong leukemia reactivity during cytokine-optimized short to intermediate (i.e., 2-8 weeks) culture periods. Single doses of CTL were intravenously infused into NOD/scidIL2Rcg(null) mice when engraftment with patient AML reached bone marrow infiltration of 1-5%, clinically defining minimal residual disease status. This treatment resulted in complete regression of HLA-mismatched and strong reduction of HLA-matched AML infiltration, respectively. Most importantly, mice receiving AML-reactive CTL showed significantly prolonged survival. Transferred CTL were detectable in murine bone marrow and spleen and demonstrated sustained AML-reactivity ex vivo. Moreover, injections with human IL-15 clearly promoted CTL persistence. In summary, we show that naive donor-derived CD8(+) CTL effectively combat patient AML blasts in immunodeficient mice. The donor-patient specific humanized mouse model appears suitable to evaluate therapeutic efficacy of AML-reactive CTL before adoptive transfer into patients. It may further help to identify powerful leukemia rejection antigens and T-cell receptors for redirecting immunity to leukemias even in a patient-individualized manner.
authors.affiliation: Department of Medicine III-Hematology, Internal Oncology and Pneumology, University Medical Center of Johannes Gutenberg-University Mainz, Langenbeckstr.1, Mainz, 55101, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Distler
authors.affiliation: Department of Medicine III-Hematology, Internal Oncology and Pneumology, University Medical Center of Johannes Gutenberg-University Mainz, Langenbeckstr.1, Mainz, 55101, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Albrecht
authors.affiliation: Department of Medicine III-Hematology, Internal Oncology and Pneumology, University Medical Center of Johannes Gutenberg-University Mainz, Langenbeckstr.1, Mainz, 55101, Germany.
authors.forename: Ariane
authors.initials: A
authors.lastname: Brunk
authors.affiliation: Department of Medicine III-Hematology, Internal Oncology and Pneumology, University Medical Center of Johannes Gutenberg-University Mainz, Langenbeckstr.1, Mainz, 55101, Germany.
authors.forename: Shamsul
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Medicine III-Hematology, Internal Oncology and Pneumology, University Medical Center of Johannes Gutenberg-University Mainz, Langenbeckstr.1, Mainz, 55101, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Schnürer
authors.affiliation: Department of Medicine III-Hematology, Internal Oncology and Pneumology, University Medical Center of Johannes Gutenberg-University Mainz, Langenbeckstr.1, Mainz, 55101, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Frey
authors.affiliation: Institute of Pathology, Julius-Maximilians-University Würzburg, Josef-Schneider-Str. 2, Würzburg, 97080, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Mottok
authors.affiliation: Department of Medicine II, Julius-Maximilians-University Würzburg, Josef-Schneider-Str. 2, Würzburg, 97080, Germany.|Interdisziplinary Center for Clinical Research (IZKF), Zinklesweg 10, Würzburg, 97078, Germany.
authors.forename: Ana-Laura
authors.initials: AL
authors.lastname: Jordán-Garrote
authors.affiliation: Department of Medicine II, Julius-Maximilians-University Würzburg, Josef-Schneider-Str. 2, Würzburg, 97080, Germany.|Interdisziplinary Center for Clinical Research (IZKF), Zinklesweg 10, Würzburg, 97078, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Brede
authors.affiliation: Department of Medicine II, Julius-Maximilians-University Würzburg, Josef-Schneider-Str. 2, Würzburg, 97080, Germany.|Interdisziplinary Center for Clinical Research (IZKF), Zinklesweg 10, Würzburg, 97078, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Beilhack
authors.affiliation: Department of Medicine III-Hematology, Internal Oncology and Pneumology, University Medical Center of Johannes Gutenberg-University Mainz, Langenbeckstr.1, Mainz, 55101, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mades
authors.affiliation: Department of Medicine III-Hematology, Internal Oncology and Pneumology, University Medical Center of Johannes Gutenberg-University Mainz, Langenbeckstr.1, Mainz, 55101, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Tomsitz
authors.affiliation: Department of Medicine III-Hematology, Internal Oncology and Pneumology, University Medical Center of Johannes Gutenberg-University Mainz, Langenbeckstr.1, Mainz, 55101, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Theobald
authors.affiliation: Department of Medicine III-Hematology, Internal Oncology and Pneumology, University Medical Center of Johannes Gutenberg-University Mainz, Langenbeckstr.1, Mainz, 55101, Germany.|Department of Medicine III-Hematology and Internal Oncology, University Hospital of Regensburg, Franz-Josef-Strauß-Allee 11, Regensburg, 93053, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Herr
authors.affiliation: Department of Medicine III-Hematology, Internal Oncology and Pneumology, University Medical Center of Johannes Gutenberg-University Mainz, Langenbeckstr.1, Mainz, 55101, Germany.|Research Center for Immunotherapy, University Medical Center of Johannes Gutenberg-University Mainz, Langenbeckstr. 1, Mainz, 55101, Germany.
authors.forename: Udo F
authors.initials: UF
authors.lastname: Hartwig
mesh_terms: D000818:Animals; D020544:Graft vs Leukemia Effect; D015235:HLA-B Antigens / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D016219:Immunotherapy, Adoptive; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000628:therapy*; D051379:Mice; D018365:Neoplasm, Residual; D057285:Precision Medicine; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D015235:HLA-B Antigens
keywords: Allogeneic hematopoietic stem cell transplantation; CD45RA-derived cytolytic T lymphocytes; acute myeloid leukemia; adoptive T-cell therapy; donor-patient specific humanized mouse model; patient-individualized immunotherapy