Modulation of Immune Checkpoints and Graft-versus-Leukemia in Allogeneic Transplants by Antagonizing Vasoactive Intestinal Peptide Signaling

Abstract

The goal of allogeneic bone marrow transplantation (allo-BMT) is elimination of leukemia cells through the graft-versus-leukemia (GvL) activity of donor cells, while limiting graft-versus-host disease (GvHD). Immune checkpoint pathways regulate GvL and GvHD activities, but blocking antibodies or genetic inactivation of these pathways can cause lethal GVHD. Vasoactive intestinal peptide (VIP) is an immunosuppressive neuropeptide that regulates co-inhibitory pathways; its role in allo-BMT has not been studied. We found VIP transiently expressed in donor NK, NK-T, dendritic cells (DC) and T-cells after allo-transplant, as well as host leukocytes. A peptide antagonist of VIP-signaling (VIPhyb) increased T-cell proliferation in vitro and reduced IL10 expression in donor T-cells. Treatment of allo-BMT recipients with VIPhyb, or transplanting donor grafts lacking VIP (VIP-KO), activated donor T-cells in lymphoid organs, reduced T-cell homing to GvHD target organs, and enhanced GvL without increasing GvHD in multiple allo-BMT models. Genetic or ex vivo depletion of donor NK cells or CD8+ T-cells from allografts abrogated the VIPhyb-enhanced GvL activity. VIPhyb treatment led to down-regulation of PD-1 and PD-L1 expression on donor immune cells, increased effector molecule expression, and expanded oligoclonal CD8+ T-cells that protected secondary allo-transplant recipients from leukemia. Blocking VIP-signaling thus represents a novel pharmacological approach to separate GvL from GvHD and enhance adaptive T cell responses to leukemia-associated antigens in allo-BMT.

Improving T-cell expansion and function for adoptive T-cell therapy using ex vivo treatment with PI3Kδ inhibitors and VIP antagonists

“…[44][45][46][47][48] T cells expanded in VIPhyb alone had significantly increased antitumor activity, consistent with prior reports that VIPhyb enhances both autologous antitumor T-cell responses and graft-versus-leukemia responses in murine leukemia models. 13,14 Utilizing an alternative approach to block VIP signaling through cleavage of endogenously produced VIP peptide with mast cell chymase gave similar results (supplemental Figure 6). 49 One mechanism by which VIP exerts its anti-inflammatory effect is through phosphorylation and activation of CREB, reducing downstream nuclear factor kB signaling.…”

“…Since the net expansion of T cells expanded in culture with anti-CD3/CD28 beads for 10 to 14 days is much less than what would be predicted based upon the cell cycle length of optimally activated T cells expanding in vivo to antigen, we hypothesized that adding agents that decrease activation-induced terminal differentiation and cell death [8][9][10] and a peptide competitive antagonist of vasoactive intestinal polypeptide (VIP) that reverse immune suppression caused by native VIP 11,12 would have favorable effects on net expansion of T cells with cytotoxic activity in vivo. The rationale for using these agents was previous data from our laboratory showing enhancement of CD8 T-cell dependent anticancer immunity in peptide antagonist to vasoactive intestinal peptide (VIPhyb)-treated mice 13,14 and reports of autoimmunity after stopping PI3K d inhibitor (idelalisib) in lymphoma and chronic lymphocytic leukemia (CLL) patients. [15][16][17] To test this hypothesis, we studied blood samples from healthy volunteers, DLBCL patients prior to treatment, and samples from DLBCL patients who had received multiple courses of cytotoxic treatment.…”

Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice

“…These findings suggest that reduction in PD-1 on CD8 1 T cells does not necessarily exacerbate GVHD as reported previously by others. 63 One of the most notable features of human cGVHD is skin damage and scleroderma, which occur in up to 75% of cGVHD patients. 64 Thus, we sought to test if targeting XBP-1 would also be efficacious in a minor-antigen mismatched cutaneous model of cGVHD.…”

Interfering with MIF-CD74 signalling on macrophages and dendritic cells with a peptide-based approach restores the immune response against metastatic melanoma

“…However, in the field of drug discovery, peptide based approaches emerge with intrinsic advantages, compared to antibodies including their small size, lack of immunogenicity, high affinity, specificity to different targets, low toxicity, good tissue penetration and biocompatibility (22,25,26). Peptides can exert immunomodulatory functions and have been shown to neutralize immune checkpoint receptors in cancer (68)(69)(70). Indeed, linear peptides such as CDR peptides are flexible and likely to bind to different biologically relevant targets (41).…”