Distler, Eva and Albrecht, Jana and Brunk, Ariane and Khan, Shamsul and Schnuerer, Elke and Frey, Michaela and Mottok, Anja and Jordan-Garrote, Ana-Laura and Brede, Christian and Beilhack, Andreas and Mades, Andreas and Tomsitz, Dirk and Theobald, Matthias and Herr, Wolfgang and Hartwig, Udo F. (2016) Patient-individualized CD8(+) cytolytic T-cell therapy effectively combats minimal residual leukemia in immunodeficient mice. INTERNATIONAL JOURNAL OF CANCER, 138 (5). pp. 1256-1268. ISSN 0020-7136, 1097-0215
Full text not available from this repository. (Request a copy)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 1 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 1 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACUTE MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; ALLOGENEIC BONE-MARROW; STEM-CELLS; IN-VIVO; LYMPHOCYTIC-LEUKEMIA; ANTITUMOR IMMUNITY; RELAPSED LEUKEMIA; NAIVE PRECURSORS; TUMOR-REGRESSION; Allogeneic hematopoietic stem cell transplantation; adoptive T-cell therapy; acute myeloid leukemia; CD45RA-derived cytolytic T lymphocytes; patient-individualized immunotherapy; donor-patient specific humanized mouse model |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 11 Mar 2019 14:44 |
| Last Modified: | 11 Mar 2019 14:44 |
| URI: | https://pred.uni-regensburg.de/id/eprint/2378 |
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