PLZF Confers Effector Functions to Donor T Cells That Preserve Graft-versus-Tumor Effects while Attenuating GVHD

Abstract

Efforts to limit graft-versus-host disease (GVHD) mediated by alloreactive donor T cells after allogeneic bone marrow transplantation (allo-BMT) are limited by a concomitant decrease in graft-versus-tumor (GVT) activity and increased possibilities of tumor relapse. Using a novel approach, we adoptively transferred conventional T cells expressing the transcription factor promyelocytic leukemia zinc finger (PLZF), which confers effector properties resembling invariant natural killer T cells (iNKT cells), such as copious production of cytokines under suboptimal stimulation. PLZF expression in T cell allografts attenuates expansion of alloreactive T cells, leading to lower GVHD. Intact alloreactivity-driven antitumor cytokine responses result in preserved GVT effects leading to improved survival. Our findings suggest that therapy with PLZF-overexpressing T cells would result in overall improved outcomes due to less GVHD and intact GVT effects.

Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity

“…They were co-housed in three to five mice/cage in all experiments. Mouse HSCT experiments with a MHC disparate model (B6 → BALB/c) and a haploidentical model (B6 → CBF1) have been used extensively by others as well as by us 2,3 . The chronic GVHD model (B6 → B10.BR) has been described in detail previously 4 .…”

“…Animals with scores greater than five were euthanized. Blinded histopathological assessment of GVHD in liver, small intestine, and large intestine was performed at Massachusetts General Hospital (Boston, Massachusetts, USA), and University of Florida (Gainesville, Florida, USA) as previously described 2 .…”

“…A20-TGL and T cells from luciferase-expressing mice (a gift from Robert Negrin, Stanford University, Palo Alto, California, USA) were visualized using in vivo bioluminescence imaging systems (Caliper Life Sciences) 2 . The bioluminescent flux was analyzed using Living Image software, version 4.3 (Caliper Life Sciences).…”

“…We performed experiments in acute GVHD models comprising MHC-disparate (B6→BALB/c) 19 and haploidentical (B6→CBF1) 20 combinations to determine if the inhibition of GVHD by the m1928z T cells was consistent in mice on different genetic backgrounds with heterogeneous alloreactive TCR antigen specificities. Histopathological analyses revealed significantly lower GVHD scores in major GVHD target organs (skin, liver, small and large intestines) of allo-HSCT recipients of m1928z vs. m19delta T in both transplant models (Figure 1G).…”

Genetically engineered donor T cells to optimize graft‐versus‐tumor effects across MHC barriers

“…To explore the potential of PLZF expressing T cells as immunotherapeutic agent in the context of allo-HSCT, we administered allo-HSCT recipient mice with PLZF transgenic (PLZF-TG) conventional T cells in murine GVHD models and found that PLZF-TG T cells did not elicit significant GVHD lethality or morbidity (85). Such an attenuated GVHD was associated with a hyperactivated state of alloreactive T cells that were highly susceptible to cell death.…”