Engineering hematopoietic grafts: Purified allogeneic hematopoietic stem cells plus expanded CD8+ NK-T cells in the treatment of lymphoma

Michael R. Verneris, Maki Ito, Jeanette Baker, Arash Arshi, Robert S. Negrin, Judith A. Shizuru

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

A major benefit of allogeneic hematopoietic cell transplantation (HCT) in the treatment of malignancies is the graft-versus-tumor (GVT) effect conferred by lymphocytes contained within the graft. However, lymphocytes can also induce the potentially lethal complication of graft-versus-host disease (GVHD). We have previously reported a method of generating large numbers of ex vivo activated and expanded T cells with antitumor activity after culture with interferon-γ, cross-linking antibodies to CD3, and interleukin-2. Murine splenocytes expanded under these conditions are a heterogeneous population of which approximately 20% to 60% of cells express natural killer (NK)-cell markers (NK1.1 and DX5) and display major histocompatibility complex (MHC)-unrestricted antitumor activity. Here we demonstrate the in vivo antitumor activity of this population of expanded CD8+ NK-T cells when transplanted across MHC barriers into tumor-bearing hosts. In cotransfer studies with purified allogeneic hematopoietic stem cells, expanded CD8+ NK-T cells confer GVT activity with minimal to no GVHD. In vitro studies show that, although expanded NK-T cells lyse normal allogeneic bone marrow cells, they preferentially mediate cytolysis against tumor targets. These cells persist in the peripheral circulation of host animals for at least 3 weeks posttransfer. GVT activity is dependent on perforin, but not on Fas-ligand. We conclude that expanded CD8+ NK-T cells may serve as a valuable adjuvant population for allogeneic HCT because they mediate GVT effects with minimal GVHD.

Original languageEnglish (US)
Pages (from-to)532-542
Number of pages11
JournalBiology of Blood and Marrow Transplantation
Volume7
Issue number10
DOIs
StatePublished - 2001

Bibliographical note

Funding Information:
This work was supported by NIH grant CA8006-01 (R.S.N.), NCI grant CA49605 (R.S.N. and J.A.S.), the American Society of Hematology (M.R.V.), and the Burroughs Welcome Fund (J.A.S.).

Keywords

  • Expanded CD8 NK-T cells
  • GVHD
  • Graft-versus-tumor effect
  • Hematopoietic cell transplantation
  • Hematopoietic stem cell
  • Lymphoma
  • Mice

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