Graft-versus-leukemia effect of HLA-haploidentical central-memory t-cells expanded with leukemic APCs and modified with a suicide gene

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)466-475
Number of pages10
JournalMolecular Therapy
Volume21
Issue number2
DOIs
Publication statusPublished - Feb 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

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