Thiolat and Pilon et al. evaluated two human IL-2/anti-IL-2 complexes in an allo-HSCT setting. When administered early and for a short time period, Cx25 (a pro-Treg complex preferentially activating Tregs bearing IL-2Rαβγ) and Cx122 (a pro-T effector complex preferentially activating IL-2Rαβ+ CD4+ and CD8+ T cells, and NK cells) both prevented GvHD development via Treg expansion and reduction of CD8+ T cells in a semi-allogeneic HSCT model. However, only Cx25 additionally induced a decrease in the proportion of exhausted CD8+ T cells and promoted a GvL effect, while still preventing GvHD, even in a xeno-GvHD model.
Contributed by Ute Burkhardt
ABSTRACT: Modulating an immune response in opposite directions represents the holy grail in allogeneic hematopoietic stem cell transplantation (allo-HSCT) to avoid insufficient reactivity of donor T cells and hematologic malignancy relapse while controlling the potential development of graft-versus-host disease (GVHD), in which donor T cells attack the recipient's tissues. IL-2/anti-IL-2 complexes (IL2-Cxs) represents a therapeutic option to selectively accentuate or dampen the immune response. In dedicated experimental models of allo-HSCT, including also human cells injected in immunodeficient NSG mice, we evaluated side-by-side the therapeutic effect of two IL-2Cxs designed either to boost regulatory T cells (Tregs) or alternatively to activate effector T cells (Teffs), on GVHD occurrence and tumor relapse. We also evaluated the effect of the complexes on the phenotype and function of immune cells in vivo. Unexpectedly, both pro-Treg and pro-Teff IL-2Cxs prevented GVHD development. They both induced Treg expansion and reduced CD8+ T cells numbers, compared to untreated mice. However, only mice treated with the pro-Treg IL-2Cx, showed a dramatic reduction of exhausted CD8+ T cells, consistent with a potent anti-tumor effect. When evaluated on human cells, pro-Treg IL-2Cx also preferentially induced Treg expansion in vitro and in vivo, while allowing the development of a potent antitumor effect in NSG mice. Our results demonstrated the clinical relevance of using a pro-Treg, but not a pro-Teff IL2/anti-IL-2 complex to modulate alloreactivity after HSCT, while promoting a GVL effect.
Author Info: (1) Univ Paris Est Crteil, INSERM U955, IMRB, F-94010 Crteil. (2) Univ Paris Est Crteil, INSERM U955, IMRB, F-94010 Crteil, France; AP-HP, Groupe hospitalo-universitaire Chenev
Author Info: (1) Univ Paris Est Crteil, INSERM U955, IMRB, F-94010 Crteil. (2) Univ Paris Est Crteil, INSERM U955, IMRB, F-94010 Crteil, France; AP-HP, Groupe hospitalo-universitaire Chenevier Mondor, Centre d'Investigation Clinique Biothrapie, Fdration hospitalo-Universitaire TRUE, F-94010 Crteil. (3) INSERM U932, PSL Research University, Institute Curie Research Center, Paris, France; Department of Translational Research, PSL Research University, Institut Curie Research Center, Paris. (4) Univ Paris Est Crteil, INSERM U955, IMRB, F-94010 Crteil. (5) Univ Paris Est Crteil, INSERM U955, IMRB, F-94010 Crteil. (6) INSERM U932, PSL Research University, Institute Curie Research Center, Paris, France; Department of Translational Research, PSL Research University, Institut Curie Research Center, Paris. (7) Univ Paris Est Crteil, INSERM U955, IMRB, F-94010 Crteil, France; AP-HP, Groupe Hospitalo-Universitaire Chenevier Mondor, Service d'Hmatologie Clinique, F-94010 Crteil. (8) Univ Paris Est Crteil, INSERM U955, IMRB, F-94010 Crteil, France; AP-HP, Groupe hospitalo-universitaire Chenevier Mondor, Centre d'Investigation Clinique Biothrapie, Fdration hospitalo-Universitaire TRUE, F-94010 Crteil, France; AP-HP, Groupe Hospitalo-Universitaire Chenevier Mondor, Service d'Hmatologie Clinique, F-94010 Crteil. (9) INSERM U932, PSL Research University, Institute Curie Research Center, Paris, France; Department of Translational Research, PSL Research University, Institut Curie Research Center, Paris. (10) Univ Paris Est Crteil, INSERM U955, IMRB, F-94010 Crteil, France; AP-HP, Groupe hospitalo-universitaire Chenevier Mondor, Centre d'Investigation Clinique Biothrapie, Fdration hospitalo-Universitaire TRUE, F-94010 Crteil. jose.cohen@inserm.fr.
