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-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.

Blazing a new TRAIL in hematopoietic cell transplantation

“…This manuscript advances the field of cellular therapy by documenting the potential of separating GVHD from GVL: the prevention of GVHD not only without loss of GVL, but actual enhancement of GVL. used these cells in adoptive transfer experiments (6). As expected, they observed that TRAIL + T cells were highly active in vitro and in vivo in a murine model.…”

“…As mentioned above, cells overexpressing TRAIL could also be quite useful as an "off-the-shelf" third-party infusion following lymphodepletion in a patient, resulting in GVL activity during the lymphopenic period, followed by rejection of the allogeneic TRAIL + cells after recovery of host immunity. Indeed, the work by Ghosh et al (6) suggests that TRAIL + T cells could exert their antitumor effects during this period of lymphodepletion, ridding the patient of the malignancy without altering their ability to fight viral infections. This manuscript advances the field of cellular therapy by documenting the potential of separating GVHD from GVL: the prevention of GVHD not only without loss of GVL, but actual enhancement of GVL.…”

“…The authors suggest that this may be related to increased cytotoxicity of the TRAIL + T cells (6), but the molecular details of this remain to be elucidated. Last, it would be useful to know how long these cells would persist in vivo, as continued survival of TRAIL + T cells would result in to successful allogeneic stem cell transplantation, and the prevention of GVHD while preserving GVL is the holy grail of research in this field.…”

“…In this issue of the JCI, Ghosh et al present tantalizing data to suggest that it may be possible to actually enhance GVL without increasing the risk of developing GVHD (6). This group previously demonstrated that TNF-related apoptosis-inducing ligand (TRAIL) is required for optimal GVL activity (7).…”

Impact of C-rel inhibition of cord blood-derived B-, T-, and NK cells

“…Over the years, the concept of allo-HSCT has shifted toward a strategy of graft-versus-tumor (GVT) activity (Jenq & van den Brink 2010;Ghosh et al 2013Ghosh et al , 2014. Since GVH outcomes are often a complication of allo-HSCT, resulting in significant morbidity and mortality, and strategies to suppress GVH often result in broad immunosuppression (leading to immune deficiency/compromised anti-tumor surveillance), it has been important to explore targeting of molecular pathways that could accomplish separation of GVHD from GVT activity.…”