title: Graft-versus-leukemia effect of HLA-haploidentical central-memory T-cells expanded with leukemic APCs and modified with a suicide gene.
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 (T(CM)) 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.
authors.affiliation: Experimental Hematology Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Casucci
authors.forename: Serena Kimi
authors.initials: SK
authors.lastname: Perna
authors.forename: Laura
authors.initials: L
authors.lastname: Falcone
authors.forename: Barbara
authors.initials: B
authors.lastname: Camisa
authors.forename: Zulma
authors.initials: Z
authors.lastname: Magnani
authors.forename: Massimo
authors.initials: M
authors.lastname: Bernardi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Crotta
authors.forename: Cristina
authors.initials: C
authors.lastname: Tresoldi
authors.forename: Katharina
authors.initials: K
authors.lastname: Fleischhauer
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Silvia
authors.initials: S
authors.lastname: Gregori
authors.forename: Federico
authors.initials: F
authors.lastname: Caligaris Cappio
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cignetti
authors.forename: Attilio
authors.initials: A
authors.lastname: Bondanza
authors.forename: Chiara
authors.initials: C
authors.lastname: Bonini
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015774:Ganciclovir / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D041722:Genes, Transgenic, Suicide / Q000235:genetics* / Q000276:immunology; D016162:Genes, Wilms Tumor; D015316:Genetic Therapy; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology / Q000628:therapy; D020544:Graft vs Leukemia Effect / Q000235:genetics*; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D055815:Young Adult
chemical_list: D006680:HLA Antigens; D015774:Ganciclovir