Patient-individualized CD8⁺ cytolytic T-cell therapy effectively combats minimal residual leukemia in immunodeficient mice.

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.

Distler E ，Albrecht J ，Brunk A ，Khan S ，Schnürer E ，Frey M ，Mottok A ，Jordán-Garrote AL ，Brede C ，Beilhack A ，Mades A ，Tomsitz D ，Theobald M ，Herr W ，Hartwig UF ... -  《-》

Acute myeloid leukemia (AML)-reactive cytotoxic T lymphocyte clones rapidly expanded from CD8(+) CD62L((high)+) T cells of healthy donors prevent AML engraftment in NOD/SCID IL2Rgamma(null) mice.

Distler E ，Wölfel C ，Köhler S ，Nonn M ，Kaus N ，Schnürer E ，Meyer RG ，Wehler TC ，Huber C ，Wölfel T ，Hartwig UF ，Herr W ... -  《EXPERIMENTAL HEMATOLOGY》

HLA-DPB1 mismatch alleles represent powerful leukemia rejection antigens in CD4 T-cell immunotherapy after allogeneic stem-cell transplantation.

Herr W ，Eichinger Y ，Beshay J ，Bloetz A ，Vatter S ，Mirbeth C ，Distler E ，Hartwig UF ，Thomas S ... -  《-》

Clinical grade expansion of CD45RA, CD45RO, and CD62L-positive T-cell lines from HLA-compatible donors: high cytotoxic potential against AML and ALL cells.

Barbui AM ，Borleri G ，Conti E ，Ciocca A ，Salvi A ，Micò C ，Introna M ，Rambaldi A ... -  《EXPERIMENTAL HEMATOLOGY》

Adoptive transfer of PR1 cytotoxic T lymphocytes associated with reduced leukemia burden in a mouse acute myeloid leukemia xenograft model.

Ma Q ，Wang C ，Jones D ，Quintanilla KE ，Li D ，Wang Y ，Wieder ED ，Clise-Dwyer K ，Alatrash G ，Mj Y ，Munsell MF ，Lu S ，Qazilbash MH ，Molldrem JJ ... -  《-》