Pilo lot T Tria ial l Examin ining M Myelo eloid-Der erived ed Suppressor C Cells a and I Immune Checkpoint Regulators' E s' Express ession i in A n Allogen enei eic S Stem em Cell T Transp splant R Recipien ents s Using Myeloablative B Busulfan a and F Fludarabine Rodwell Mabaera, MD Norris Cotton Cancer Center Dartmouth Hitchcock Medical Center
Acknow owled edgem ements Authors Collaborators • Kenneth Meehan, MD Dartmouth Immune • John Hill, MD monitoring lab • Christi Hayes MD. • Christopher Lowrey MD Funding • Randy Noelle, PhD Collaborative grant • Zbigniew Szczepiorkowski MD, PhD (Meehan/Mabaera) • Kate Wilcox RN • Lynn Root RN • Dorie McKenna Early Phase Trial Clinical Oncology Pilot Grant NCATS KL2 Scholar Grant (KL2TR001088)
Di Disc sclosu sures es • Paid consultant for Immunext Inc. on NIH grant application • No relevant financial conflict of interests to disclose with respect to this presentation • There will be no discussion of any off-label use of products
Lea earning Obj Objec ectives es • Understand GVHD as a major contributor to morbidity/Mortality that limits the application allogeneic bone marrow transplantation • Understand mechanisms that drive GVHD development and rationale for current management strategies • Understand the limitations of current GVHD treatments and importance of ongoing research to identify new biomarkers and targets for safer therapies
Outlin line • Summary of allogeneic bone marrow transplantation (ABMT) and GVHD • Role of Myeloid derived suppressor cells and immune checkpoint regulators in allo-tolerance and potential as GVHD targets • VISTA (V-domain Ig Suppressor of T cell activation) as a target in GVHD • Clinical trial preliminary data and planned follow up.
Allogeneic bone marrow transplant • Useful for treating bone marrow defects and refractory blood and other malignancies by allowing use of higher doses of chemotherapy and radiotherapy • Donor immune system prevents disease relapse (graft-versus-tumor effect) • Graft-versus-host disease (GVHD) is a major limiting complication mediated by same mechanism targeting normal recipient organs • Clinical Need: therapies specific for GVHD that do not impact immune competence and disease relapse.
Mechanisms controlling graft/host allo-tolerance • Minor MHC mismatch drives alloreactivity of donor T cells against host target organs • Host (early) and donor later) derived myeloid cells promote GVHD through inflammatory cytokines • Major negative regulators are regulatory T cells (T-regs) and Regulatory T cells myeloid-derived suppressor cells & ?other cell types (MDSCs)
T cell activation and costimulation in GvHD ? ? Graft genetic polymorphisms or experimental models that alter CTLA-4 and PD-1 pathways can affect GVHD without decreasing graft vs. tumor (GVT) activity.
VISTA Summary • Immunes-restricted membrane protein belonging to B7 family. Appear to have both receptor and ligand functions • Negative check-point regulator: prevents T-cell activation and effector function. • “Antagonistic” VISTA antibodies are immune enhancing and are in development for cancer immunotherapy. • “Agonistic” antibodies are immunosuppressive in models of arthritis and lupus. • Hypothesis: Immunosuppressive anti-Vista antibodies suppress GVHD
Preliminary data: Single prophylactic anti-VISTA antibody treatment protects against GVHD. A C B Is there a role for VISTA and other immune checkpoints as biomarkers during early immune recovery and targets for GVHD therapy?
Preliminary data from clinical trial Aim: Identify what component of early immune reconstitution is associated with disease, transplant, and GVHD outcomes Enrolment Goal: 20 patients over 2 years. Predicted rate of GVHD >30% 1 AML relapsed 1 pt died of GVHD by day 60 and complications died by day 120 around day 300 17 pts Enrolled (15 have lab data) 13/15 Completed Day 8 AML 100 including seven 3 Myelofibrosis (47%) with GVHD 3 MDS 1 T-cell ALL
Early bone marrow recovery is associated with transient increase in MDSCs G r a n u l o c y t i c M D S C s - C D 1 1 b + H L A D R - C D 1 5 + ) ( L i n 4 0 3 0 % T o t a l W B C 2 0 1 0 0 0 3 0 6 0 9 0 M o n o c y t i c M D S C s - C D 1 1 b + H L A D R - C D 1 4 + ) ( L i n 5 0 4 0 % T o t a l W B C 3 0 2 0 1 0 0 0 3 0 6 0 9 0 D a y s P o s t T r a n s p l a n t
Early bone marrow recovery is associated with transient increase in MDSCs
Immunosuppressive anti-VISTA enhances MDSC suppressive function post-transplant * Proliferation index Control Ab VISTA Ab Immunosuppressive anti-VISTA antibody enhances third party T-cell suppression by graft MDSCs in vitro
Day 30 monocytic MDSC function may be impaired in patients who develop GvHD M o n o c y t i c M D S C s M o n o c y t i c M D S C s - C D 1 1 b + H L A D R - C D 1 4 + ) - C D 1 1 b + H L A D R - C D 1 4 + ) ( L i n ( L i n p=0.060 N o G V H D ( n = 8 ) 5 0 1 0 G V H D ( n = 7 ) 4 0 8 + % A r g i n a s e - 1 % T o t a l W B C 3 0 6 *p = 0.047 * 2 0 4 1 0 2 0 0 0 0 0 0 0 0 0 3 6 3 6 0 1 1 D a y s P o s t T r a n s p l a n t D a y s P o s t T r a n s p l a n t
Summary 1. Early bone marrow recovery is associated with transient increase in MDSCs 2. Early (Day 30) monocytic MDSC activity may be impaired in patients with GVHD and could be a potential marker of GVHD risk. - no change in T regs , granulocytic MDSCs, or CTLA4/PD1/PDL1 expression 3. VISTA is a potential target in GVHD - Highly expressed on recovering immune cells post transplant -Prophylactic anti-vista protects 100% of mice in an acute GVHD model -Anti-VISTA enhances function of post-transplant (mostly donor- derived) MDSCs in vitro
Ongoing/Follow up Studies 1. Outcomes for clinical trial Correlation with laboratory findings 2. GVHD Biomarkers - MDSC function (engraftment to day 30) -MDSC and T cell transcriptome 3. VISTA as a target in GVHD Activity of human anti-VISTA antibody using NOD-scid IL‐2Rγnull (NSG) mice engrafted with human PBMC (humanized xeno-GVHD). 4. Impact of anti-VISTA in long term immunity
Acknow owled edgem ements Authors Collaborators • Kenneth Meehan, MD Dartmouth Immune • John Hill, MD monitoring lab • Christi Hayes MD. • Christopher Lowrey MD Funding • Randy Noelle, PhD Collaborative grant • Zbigniew Szczepiorkowski MD, PhD (Meehan/Mabaera) • Kate Wilcox RN • Lynn Root RN • Dorie McKenna Early Phase Trial Clinical Oncology Pilot Grant NCATS KL2 Scholar Grant (KL2TR001088)
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