Submitted July 22, 2008
Accepted August 21, 2008
Adoptive transfer of allogeneic tumor-specific T cells mediate effective regression of large tumors across major histocompatibility barriers
Andrea Boni, Pawel Muranski, Lydie Cassard, Claudia Wrzesinski, Chrystal M Paulos, Douglas C Palmer, Luca Gattinoni, Christian S Hinrichs, Chi-Chao Chan, Steven A Rosenberg, and Nicholas P Restifo*
Clinical Research Center, NIH/NCI, Bethesda, MD, United States
National Eye Institute, NIH, Bethesda, MD, United States
* Corresponding author; email: restifo{at}nih.gov.
Graft-versus-tumor (GVT) effects can be achieved after allogeneic bone marrow transplant (BMT) in patients with malignancies of the kidney or hematopoietic system, but are often accompanied by severe graft-versus-host-disease (GVHD). We sought to maximize GVT while minimizing GVHD using tumor-specific allogeneic effector T cells rather than open-repertoire T cells. We transferred allogeneic CD8+ pmel-1 or CD4+ TRP-1 T cells specific for the melanoma-associated antigens, gp100 and TRP-1 respectively, into B16-melanoma-bearing mice. Mice receiving a preparative regimen of non-myeloablating (5Gy) total body irradiation (TBI) experienced the rapid rejection of tumor-specific allogeneic lymphocytes with no impact on tumor growth. However, when mice were given more intense TBI conditioning regimens combined with autologous BMT, adoptively transferred allogeneic tumor-specific T lymphocytes persisted at detectable levels for several weeks and mediated significant regression of large, vascularized tumors. We found that the risk of GVHD was low when tumor-specific T cells were transferred and significant toxicity was observed only when substantial numbers of open repertoire allogeneic naive T cells were mixed with the tumor-specific lymphocytes. Taken together, these data indicate that the use of tumor-specific allogeneic, CD8+ T cells or CD4+ can result in significant anti-tumor effects in the absence of measurable GVHD.
