Journal Article

Adoptively transferred TRAIL super( +) T cells suppress GVHD and augment antitumor activity

Young, Lauren F, Penack, Olaf, Liu, Chen, Murphy, George F, Tannenbaum, Daniel, Hanash, Alan M, Yim, Nury L, van den Brink, Marcel R M, Jenq, Robert R, Piersanti, Kelly, Velardi, Enrico, Dogan, Yildirim, Ghosh, Arnab, Palomba, M Lia, Sauer, Martin G, Masih, Durva, Moroz, Maxim, Lezcano, Cecilia, Smith, Odette M, Rao, Uttam K, Holland, Amanda M, Tsai, Jennifer J, Sadelain, Michel, Ponomarev, Vladimir

2013

Overview

Current strategies to suppress graft-versus-host disease (GVHD) also compromise graft-versus-tumor (GVT) responses. Furthermore, most experimental strategies to separate GVHD and GVT responses merely spare GVT function without actually enhancing it. We have previously shown that endogenously expressed TNF-related apoptosis-inducing ligand (TRAIL) is required for optimal GVT activity against certain malignancies in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to model a donor-derived cellular therapy, we genetically engineered T cells to overexpress TRAIL and adoptively transferred donor-type unsorted TRAIL super( +) T cells into mouse models of allo-HSCT. We found that murine TRAIL super( +) T cells induced apoptosis of alloreactive T cells, thereby reducing GVHD in a DR5-dependent manner. Furthermore, murine TRAIL super( +) T cells mediated enhanced in vitro and in vivo antilymphoma GVT response. Moreover, human TRAIL super( +) T cells mediated enhanced in vitro cytotoxicity against both human leukemia cell lines and against freshly isolated chronic lymphocytic leukemia (CLL) cells. Finally, as a model of off-the-shelf, donor-unrestricted antitumor cellular therapy, in vitro-generated TRAIL super( +) precursor T cells from third-party donors also mediated enhanced GVT response in the absence of GVHD. These data indicate that TRAIL-over-expressing donor T cells could potentially enhance the curative potential of allo-HSCT by increasing GVT response and suppressing GVHD.