Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity
Arnab Ghosh, … , Vladimir Ponomarev, Marcel R.M. van den Brink
Arnab Ghosh, … , Vladimir Ponomarev, Marcel R.M. van den Brink
Published May 15, 2013
Citation Information: J Clin Invest. 2013;123(6):2654-2662. https://doi.org/10.1172/JCI66301.
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Research Article

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

Abstract

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+ T cells into mouse models of allo-HSCT. We found that murine TRAIL+ T cells induced apoptosis of alloreactive T cells, thereby reducing GVHD in a DR5-dependent manner. Furthermore, murine TRAIL+ T cells mediated enhanced in vitro and in vivo antilymphoma GVT response. Moreover, human TRAIL+ 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#x02013;generated TRAIL+ precursor T cells from third-party donors also mediated enhanced GVT response in the absence of GVHD. These data indicate that TRAIL-overexpressing donor T cells could potentially enhance the curative potential of allo-HSCT by increasing GVT response and suppressing GVHD.

Authors

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

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Figure 6

Genetically engineered TRAIL+ huT cells have increased GVT potential and can suppress activated T cells.

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Genetically engineered TRAIL+ huT cells have increased GVT ...
(A) Representation of SFG-huTRAIL-GFP construct: SFG-huTRAIL-IRES-GFP. SFG-CBRLuc-IRES-GFP was used as a GFP control. (B) Prestimulated huT cells were transduced and transduction was measured by the expression of GFP. (C#x02013;E) 51Cr release assays comparing tumor cytolysis between GFP+ and TRAIL+ huT cells against the (C) K562 cell line and PBMCs derived from CLL patients (D) CLL-1 and (E) CLL-2. (F) 51Cr release assay comparing cytolysis mediated by GFP+ and TRAIL+ huT cells against activated T cells. Representative graphs of at least 3 assays are shown. *P lt; 0.05; **P lt; 0.01; ***P lt; 0.001; ****P lt; 0.0001. IRES, internal ribosome entry site.