Graft-versus-leukemia Effect of HLA-haploidentical Central-memory T-cells Expanded With Leukemic APCs and Modified With a Suicide Gene |
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| Authors: | Monica Casucci Serena Kimi Perna Laura Falcone Barbara Camisa Zulma Magnani Massimo Bernardi Alessandro Crotta Cristina Tresoldi Katharina Fleischhauer Maurilio Ponzoni Silvia Gregori Federico Caligaris Cappio Fabio Ciceri Claudio Bordignon Alessandro Cignetti Attilio Bondanza Chiara Bonini |
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| Institution: | 1. Experimental Hematology Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy;2. Hematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy;3. Molecular and Functional Immunogenetics Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy;4. Pathology Unit, San Raffaele Scientific Institute, Milan, Italy;5. Tolerogenic Dendritic Cells Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy and, Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy;6. Department of OncoHematology, Division of Molecular Oncology, San Raffaele Scientific Institute, Milan, Italy;7. Vita-Salute San Raffaele University, Milan, Italy;8. MolMed SpA, Milan, Italy;9. Tumor Immunology Unit, Institute for Cancer Research and Treatment, Candiolo, Italy;10. Current address: Center for Cell and Gene Therapy, Baylor College of Medicine, Methodist Hospital and Texas Children''s Hospital, Houston, Texas, USA |
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| Abstract: | Allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)-haploidentical family donor (haplo-HSCT) is a readily available and potentially curative option for high-risk leukemia. In haplo-HSCT, alloreactivity plays a major role in the graft-versus-leukemia (GVL) effect, which, however, is frequently followed by relapse due to emerging leukemic cell variants that have lost the unshared HLA haplotype as a mechanism of immune escape. We report that stimulation of HLA-haploidentical donor T lymphocytes with leukemic antigen-presenting cells (L-APCs) expands a population of leukemia-reactive T cells, which, besides alloreactivity to unshared HLAs, contain leukemia-associated specificities restricted by shared HLAs. According to a preferential central-memory (TCM) phenotype and to high interleukin (IL)-7Rα expression, these T cells persist in vivo and sustain a major GVL effect in a clinically relevant xenograft model. Moreover, we demonstrate that modifying L-APC–expanded T cells to express the herpes simplex virus thymidine kinase (HSV-tk) suicide gene enables their elimination with the prodrug ganciclovir (GCV), therefore providing a safety switch in case of graft-versus-host disease (GVHD). These results warrant the clinical investigation of L-APC–expanded T cells modified with a suicide gene in the setting of haplo-HSCT. |
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