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Paola Neri, MD, PhD
Associate Professor of Medicine
University of Calgary
Arnie Charbonneau Cancer Institute
How to optimize immunotherapy
approaches in Myeloma
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Paola Neri MD, PhD
• Grants/research support: MMRF, CIHR, LLS
• Speakers bureau/honoraria: Amgen, Celgene, Janssen, Takeda
• Consulting fees: Celgene, Janssen, Takeda
Disclosures
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Immune deregulation in multiple myeloma
➢ Disease progression from MGUS to Myeloma
➢ Response to immune-based therapeutics:
✓ anti-CD38 monoclonal antibodies
✓ checkpoint inhibitors
✓ CAR-T cell therapies
Strategies to reverse immune tolerance / deregulation in
myeloma
Outline
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Mechanisms of Tumor Escape in Myeloma
• ⇣⇣⇣ expression tumor antigens
• ⇣⇣⇣ expression of HLA
costimulatory molecules
• Shedding of MHC class I chain-
related protein A (MICA)
• ⇡⇡⇡ surface inhibitory ligands
Inadequate T-cell stimulation
and Impaired cytotoxicity
• ⇣⇣⇣ CD4:CD8 ratio
• ⇣⇣⇣ of stem-like (Tscm) and effector
memory (TEM) T cells
•
• ⇡⇡⇡ in terminal effector T cells
• T-cell exhaustion /senescence
• ⇡⇡⇡ Th17
• Recruitment of IS cells (T-regs, MDSCs,
pDCs)
Induce Tumor escape
BM Milieu MM cells
Kumar S et al, Nature Reviews 2017
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MGUS is genetically similar to Myeloma with an overall lower levels of genetic abnormalities
Mikulasova A et al, Haematologica 2017
Mutational load does not vary significantly
in the transition from MGUS to MM
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Hierarchical model of human T cell differentiation
Gattinoni L et al Nature Med 2016
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Decreased memory T cells and increased terminal effectors in
MGUS & MM compared to healthy donors
Bailur J et al, JCI Insight 2019
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Expression of TCF1 is increased among memory T cells in the MGUS cohort
Decreased memory T cells stemness
in the transition from MGUS to MM
Bailur J et al, JCI Insight 2019
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Depletion of Tscm and increase in TEF/TE correlates
with progression from MGUS to MM
Bailur J et al, JCI Insight 2019
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T cells stemness is essential to repress clonal escape & sustain
effective anti-tumoral immune response
Gattinoni L, et al. Nature Reviews Cancer. 2012
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Mechanisms of resistance to anti-CD38 monoclonal antibodies:
Role of T cells
Krejick J et al Blood. 2016
Krejick J et al Blood. 2017
Caseneuf T Blood Advances 2017
Nijhof R Clin Canc Res 2014
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Daratumumab resistance in MM
Role of CD38 expression ?
Nihjov I et al Blood 2016, 128:959-970
Horenstein AL et al. Cells. 2015;4:520-537
Krejcik J et al. Clin Cancer Res; 2017; 23; 1–14
Higher CD38 expression (MFI) on myeloma cells was associated with better response ( ≳ PR) in daratumumab treated patients.
CD38 expression cannot be used as a predictor of depth or duration of response to daratumumab due to:
• overlap in CD38 expression between responders and non-responders.
• Rapid depletion in CD38 expression post daratumumab therapy in all patients.
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How does anti-CD38 therapy affect the myeloma BM Immunome?
• Serial BM aspirates (n=16) from lenalidomide refractory /relapsed patients treated with daratumumab + Pomalidomide
(MM014 trial) prior to initiation of therapy, C3D1 and at relapse.
• Paired-end sequencing; median 97,237 reads /per cell & 2599 cells per sample
• Cell Ranger Single and Seurat were used for sample de-multiplexing, barcode processing, single-cell 3′ gene counting and data
analysis. Monocle and Velocyto were applied for trajectory analysis and cell diffusion.
CD 138+ cells
CD 138 - cells
Bone Marrow
Ficoll
gradient
separation
Mononuclear
Fraction
Single-cell RNA-seq
Single-cell RNA-seq
CD3 + cellsTCR Single-cell RNA-seq
10X GemCode system
Single-cell ATAC-seq
Single-cell CNV
Single-cell ATAC-seq
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Tirosh I et al Science 2016;352:189-96
Neri P, Alberge JB, Bahlis N. Unpublished work
Daratumumab resistance & T cellsT cells subsets
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Daratumumab resistance & T cells
Neri P, Alberge JB, Maity R, Bahlis N. Unpublished work
CD27pos SELLneg Effector Memory T cells are significantly more expanded in sensitive patients
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T cells checkpoint inhibitors expression
LAG3 > TIGIT > PDCD1 > HAVCR2
Neri P, Alberge JB, Maity R, Bahlis N. Unpublished work
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Daratumumab resistance & T cell exhaustion
Neri P, Alberge JB, Maity R, Bahlis N. Unpublished work
T cells in Daratumumab and IMiDs refractory patients are largely exhausted (loss of CD28 and high expression of LAG3)
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TFs mediating exhaustion in T cells: TBX21high EOMEShigh TCF7low
Neri P, Alberge JB, Maity R, Bahlis N. Unpublished work
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Cohen A et al, JCI 2019
T-cells subsets and CART-BCMA therapy
Phase I study of autologous T cells lentivirally transduced with a fully human,
BCMA-specific CAR containing CD3ζ and 4-1BB signaling domains
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Cohen A et al, JCI 2019
CAR-T associated with
expansion and response:
1. higher CD4/CD8 T ratio
2. higher % of
CD27+CD45RO- CD8+
cell (naïve/stem cell)
Patients with higher number of naïve and stem cell memory T cells have a
robust in vivo CAR-T expansion and clinical response
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Antigen escape as mechanism of relapse
Majzer R et al, Cancer Discovery 2018
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Antigen drifting / editing and immune escape
Brudno J et al, JCO 2018
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Strategies to reverse T cells
tolerance / deregulation in multiple myeloma
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LAG3 Blockade promotes T cell activation in
an autologous myeloma and T cell co-culture systemControl Ab LAG3 blocking Ab
Neri P, Alberge JB, Maity R, Bahlis N. Unpublished work
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Miller B et al, Nature Immunology 2019
Progenitor (but not terminally) exhausted CD8+ T cells
are associated with response to checkpoint inhibitors
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Pro
port
ion
of
cyto
toxic
CD
8 T
cells
p = 0.025
GZMB expressing cytotoxic T cells
Terminally exhausted cytotoxic T cells are expanded in
Daratumumab resistant (but not sensitive) patients
Neri P, Alberge JB, Maity R, Bahlis N. Unpublished work
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TGFβ attenuates tumor response to PD-L1 blockade by contributing to exclusion of T cells
Mariathasan S et al, Nature 2018
Anti-TGFβ and anti-PD-L1 treatment promote tumor regression
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- human antigen-recognition domains to reduce immunogenicity
- bb21217 cultured with PI3 kinase inhibitor, bb007, to enrich for T cells displaying a memory-like phenotype
- TET2 modification can improve T cell stemness and persistence
Modifying manufacturing techniques to generate more phenotypically favorable
CAR-T cell
Fraietta J et al, Nature 2018
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Open clinical questions
More effective clinical responses to IOs in subjects with a less differentiated, more stem-like
rather than terminal effector T cells
o Immune modifying strategies should be applied early at diagnosis or even pre-MM
transition?
o Consider harvesting and storage of T cells early in the disease course for later use
in CAR T manufacturing?
o Continue to investigate checkpoint inhibitors in MM? appropriate selection of
checkpoint inhibitor and better predictive tools of responders.
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Acknowledgments
Collaborators
Stephane Minivielle (Nantes)
Philippe Moreau (Nantes)
Lawrence Boise (Emory)
Benjamin Barwick (Emory)
Anjan Thakurta PhD (Celgene)
Christopher Chiu PhD (Janssen)
Our Patients
Multiple Myeloma Research Foundation
Canadian Institute of Health and Research (CIHR)
Southern Alberta Multiple Myeloma Society
Funding Agencies
Dr Ranjan Maity, PhDDr Nizar Bahlis, MD Jean Baptiste Alberge, MSc