Submitted June 7, 2007
Accepted May 13, 2008
In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of anti-tumor activity
Ryosei Nishimura, Jeanette Baker, Andreas Beilhack, Robert Zeiser, Janelle A. Olson, Emanuela I Sega, Mobin Karimi, and Robert S. Negrin*
Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA, United States
* Corresponding author; email: negrs{at}stanford.edu.
Cytokine-induced killer (CIK) cells are ex vivo expanded T lymphocytes expressing both NK and T cell markers. CIK cells are cytotoxic against autologous and allogeneic tumors. We previously showed that adoptive transfer of allogeneic CIK cells in a murine model caused minimal graft-versus-host disease (GVHD). However, the precise mechanism of reduced GVHD is not fully understood. Therefore, we evaluated the trafficking and survival of luciferase-expressing CIK cells in an allogeneic bone marrow transplant model. The initial trafficking patterns of CIK cells were similar to conventional T cells that induced GVHD, however, CIK cells infiltrated GVHD target tissues much less and transiently. CIK cells accumulated and persisted in tumor sites, resulting in tumor eradication. We evaluated different properties of CIK cells compared to conventional T cells demonstrating a slower division rate of CIK cells, higher susceptibility to apoptosis, persistent increased expression of IFN-
, reduced acquisition of homing molecules allowing entry of cells into inflamed GVHD target organs which lack of expression of NKG2D ligands recognized by CIK cells. Due to these properties, allogeneic CIK cells had reduced expansion and caused less tissue damage. We conclude that CIK cells have the potential to separate graft-versus-tumor effects from GVHD.
