Pilo lot T Tria ial l Examin ining M Myelo eloid-Der erived - - PowerPoint PPT Presentation

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

Funding

Collaborative grant (Meehan/Mabaera) Early Phase Trial Clinical Oncology Pilot Grant NCATS KL2 Scholar Grant (KL2TR001088)

Acknow

• wled

edgem ements

Authors

• Kenneth Meehan, MD
• John Hill, MD
• Christi Hayes MD.
• Christopher Lowrey MD
• Randy Noelle, PhD
• Zbigniew Szczepiorkowski MD, PhD
• Kate Wilcox RN
• Lynn Root RN
• Dorie McKenna

Collaborators Dartmouth Immune monitoring lab

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

• ther malignancies by allowing use
• f 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

Regulatory T cells & ?other cell types

• 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 myeloid-derived suppressor cells (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?

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%

Preliminary data from clinical trial

1 AML relapsed by day 60 and died by day 120

13/15 Completed Day 100 including seven (47%) with GVHD

1 pt died of GVHD complications around day 300

17 pts Enrolled (15 have lab data) 8 AML 3 Myelofibrosis 3 MDS 1 T-cell ALL

3 0 6 0 9 0 1 0 2 0 3 0 4 0 5 0

M o n o c y t i c M D S C s ( L i n

• C D 1 1 b

+ H L A D R

• C D 1 4

+ )

D a y s P o s t T r a n s p l a n t % T o t a l W B C

3 0 6 0 9 0 1 0 2 0 3 0 4 0

G r a n u l o c y t i c M D S C s ( L i n

• C D 1 1 b

+ H L A D R

• C D 1 5

+ )

% T o t a l W B C

Early bone marrow recovery is associated with transient increase in MDSCs

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

3 6 1 2 4 6 8 1 0

M o n o c y t i c M D S C s ( L i n

• C D 1 1 b

+ H L A D R

• C D 1 4

+ )

D a y s P o s t T r a n s p l a n t % T o t a l W B C

Day 30 monocytic MDSC function may be impaired in patients who develop GvHD

*p = 0.047 *

3 6 1 1 0 2 0 3 0 4 0 5 0

M o n o c y t i c M D S C s ( L i n

• C D 1 1 b

+ H L A D R

• C D 1 4

+ )

D a y s P o s t T r a n s p l a n t % A r g i n a s e - 1

+

N o G V H D ( n = 8 ) G V H D ( n = 7 )

p=0.060

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 Tregs, 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

Funding

Collaborative grant (Meehan/Mabaera) Early Phase Trial Clinical Oncology Pilot Grant NCATS KL2 Scholar Grant (KL2TR001088)

Acknow

• wled

edgem ements

Authors

• Kenneth Meehan, MD
• John Hill, MD
• Christi Hayes MD.
• Christopher Lowrey MD
• Randy Noelle, PhD
• Zbigniew Szczepiorkowski MD, PhD
• Kate Wilcox RN
• Lynn Root RN
• Dorie McKenna

Collaborators Dartmouth Immune monitoring lab