Abstract 4743: Genetically engineered allogeneic T Cells for BMT immunotherapy: Expression of TRAIL and PLZF selectively enhances GVT and abrogates GVHD
Authors: Ghosh Arnab , Holland Amanda M. , Dogan Yildirim , Yim Nury , Rao Uttam K. , Young Lauren F. , Smith Odette M. , Jenq Robert , Na Il-Kang , Tsai Jennifer J. , Singer Natalie , West Mallory , Penack Olaf , Hanash Alan M. , Sant'Angelo Derek , Sadelain Michel , van den Brink Marcel RM 
Published: June 2012

Efforts to improve graft-versus-tumor (GVT) activity of alloreactive donor T cells are limited by a concomitant rise in graft-versus-host disease (GVHD). We employed experimental allogeneic bone marrow transplantation (allo-BMT) models to assess two novel strategies, in which T lineage cells were genetically engineered to enhance selective effector functions. In addition to the transgenic expression of these molecules on mature donor T cells, we also used genetically engineered precursor T cells as an “off the shelf” adoptive cell therapy.

One strategy relies on T cell cytolytic molecule TNF-Related Apoptosis Inducing Ligand (TRAIL), which induces apoptosis through death receptors (DR) 4 and 5 (only DR5 in mice). Certain tumor cells express high levels of DR5 making TRAIL an attractive candidate for engineering T cells to augment GVT. Mature T cells were transduced with a lentiviral TRAIL expression vector and adoptively transferred into lethally irradiated allogeneic bone marrow transplantation (allo-BMT) recipients, bearing LB27.4 tumors (B6 into CBF1+LB27.4). TRAIL+ T cells had enhanced antitumor effect compared to control-transduced T cells in vitro and upon transfer into tumor-bearing allo-BMT recipients (p&lt;0.01). Interestingly, the recipients of TRAIL+ T cells had significantly less GVHD. We generated TRAIL+ precursor (pre)T cells using the OP9-DL1 co-culture system. Adoptive transfer of B6 TRAIL+ preT cells into syngeneic-transplanted BALB/c mice resulted in reconstitution with TRAIL+ T cells. When challenged with localized RENCA tumors, recipients of TRAIL+ preT cells had enhanced antitumor activity (p&lt;0.05) compared to recipients of control-transduced preT cells.

The second strategy explores the effect of overexpressing the transcription factor promyelocytic leukemia zinc finger (PLZF) in T cells. PLZF transgenic (tg) T cells have an effector/memory phenotype with innate-like characteristics. Following transfer, they cells display an altered cytokine profile with increased expression of TNF-alpha and decreased IFN-gamma. Using adoptive transfer of CFSE-labeled donor T cells we observed that fast proliferating allo-responsive PLZF+ T cells died after only a few cell cycles. Using PLZF Tg mice, we found that PLZF+ T cells cause less GVHD with intact GVT activity (p&lt;0.001) against A20 lymphoma. We then transduced T cells with PLZF expression vector and confirmed that donor PLZF+ T cells have less GVHD and intact GVT activity.

Our data suggest that adoptive therapy with genetically engineered TRAIL+ or PLZF+ T cells cause less GVHD while displaying intact or enhanced GVT activity. Furthermore, the “off the shelf” use of genetically enhanced preT cells represents a promising cell therapy strategy to enhance anti-tumor activity in both autologous and allo-BMT patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4743. doi:10.1158/1538-7445.AM2011-4743