Post on 16-Sep-2020
Paola Neri, MD, PhD Associate Professor of Medicine
University of Calgary, Arnie Charbonneau Cancer Institute
Bases for Immunotherapy in Multiple Myeloma
Paola Neri MD, PhD
• Grants/research support: MMRF, CIHR, LLS• Speakers bureau/honoraria: Bristol‐Myers Squibb, Celgene, Janssen, Takeda• Consulting fees: Celgene, Janssen, Takeda
Disclosures
• The Myeloma Niche Components of Myeloma microenvironment
• Immune Dysregulation in Myeloma Mechanisms of tumor escape
• Immunotherapeutic strategies: Agents that reverse tumor‐mediated immune paralysis Agents that selectively target the malignant clone Agents that activate immune cells to target the tumor
Outline
Components of Myeloma Milieu
There is an intimate relationship between PC and BM milieu where PC are hosted in special niches and receive multiple signalsthat maintain their survival and promote drug resistance. The main components of MM niche are extracellular matrix (ECM),soluble components and hematopoietic and non‐hematopoietic cells. Shaji K Kumar et al, Nature Reviews 2017
Autocrine and paracrine loops and cell‐cell adhesion mechanisms regulate PC production of cytokines and induce signaling pathways responsible for PC survival, growth, migration and drug‐resistance.
The Myeloma Niche
Teru Hideshima et al, Nature Reviews 2007
MM evolution is known to be associated with progressive immune dysregulation and loss of immune surveillance thatfosters disease progression, drug resistance and facilitate immune escape.
Mechanisms of Tumor Escape in Myeloma
The levels of B cells, NK cells and CD4+ T cells are reduced and impaired.The main dysregulated immunological elements include DC, Treg, TH17, MDSCs, Macrophages and Plasmacytoid DCs (pDC).
Malignant Plasma cells
Bone Marrow Stromal Cells
CD28
Dendritic cells
CD80/CD86
IDO
IL‐6
T cells Treg cells OCs
Naïve CD4+ T cells
Th1
Th2
Th17
IL‐2IFN‐
IL‐10IL‐4
TGF‐IL‐6
IL‐17
CTLs
RANKL
Brown RD et al, Blood 2001Brimness MK et al, Clin Exp Immunol 2006Leone P et al, Blood 2015Nair JR et al, Oncoimmunology 2012Ogawara H et al, Leuk Res 2005Korn T et al, PNAS 2008Prabhala R et al, Blood 2010Noonan K et al, Blood 2010
Mechanisms of Tumor Escape in Myeloma
Malignant Plasma cells
Bone Marrow Stromal Cells
Treg cells
MDSCs
Arg‐1
NOS
ROS
T cellsMyeloid cells
CXCR4CXCL12
Macrophages
IL‐10IL‐1TNF‐
T cells
VEGFIL‐8FGF‐2CSF‐1
Tumor growth
Invasion
IL‐6IL‐10
M2
Plasmacytoid DCs
IL‐10, VEGFIL‐8, IL‐15 IL‐6, SDF1‐a
Tumor growth, chemotaxis and drug resistance
Nakamura K et al, Cancer Cell 2018Gabrilovich DI et al, Nat Rev Immunol 2009Gorgun GT et al, Blood 2013Rodriguez PC et al, Cancer Res 2004Malek E et al, Blood Rev 2016Biswas SK, Nat Immunol 2010Shay G et al, J Mol Med 2016Lande R et al, Ann NY Acad Sci 2010Chauhan D et al, Cancer Cell 2009
T cells
IL‐18
M2
Mechanisms of Tumor Escape in MyelomaMalignant Plasma cells
• Reduced expression of tumor antigens (WT1, Muc1)
• Reduced expression of HLA costimulatory molecules (CD40, CD80)
• Lower expression of HLA‐DR• Shed MHC class I chain‐related protein A (MICA)
Inadequate T‐cell stimulation and Impaired cytotoxicity
• Upregulation of surface inhibitory ligands (PD‐L1, LAG3, TACI)
Mediate T‐cell anergy/exhaustion
• Recruitment of immunosuppressivecells (T‐regs, MDSCs, pDCs)
Induce Tumor escape
Brown RD et al, Leuk Lymphoma 1998Jinushi M et al, PNAS 2008Paiva B et al, Leukemia 2015Iwai Y et al, PNAS 2002
Rationale for Immunotherapy in Myeloma
• Durable complete remissions reported for allogeneic stem cell transplantation• Immunologic therapy, “graft‐versus‐myeloma effect”
• Donor lymphocyte infusion rescues patients who relapse after allo‐transplant• T cell‐mediated anti‐tumor immunity
• Interferon was the first drug used to stimulate the immune system• Its efficacy was only modest
Tricot G et al, Blood 1996Bellucci R et al, Blood 2004Myeloma Trialists Collaborative groups, Br J Haematol 2001
Immunotherapeutic strategies in development in MM
Monoclonal Antibodies
Chimeric Antigen Receptor (CAR) T cells/ Bites
Immunomodulatory drugs
2) Agents that selectively target the malignant clone
3) Agents that activate immune cells to target the tumor
1) Agents that reverse tumor mediated immune paralysis
Immune CheckpointInhibitors
Passive ImmunityTargeting a receptor
Active Therapy Delivering Cells
Adjuvant TherapyImmune Booster
Truly ’Targeted’ Therapy
‘ConnectingFlights’
Risk ‘Off Target’ effects
Dendritic cell or peptide Vaccine
Neri P et al, Clinical Cancer Res 2016
IMIDs hyper/neomorphe the CUL4a‐CRBN E3 ligase to promote the proteasomal degradation of Ikaros and Aiolos releasing IKZF1transcriptional regression of IL‐2 and type I/II interferon response genes
1. Kronke J et al. Science 21032. Lu G et al. Science 20133. Neri P et al Blood 2015
IKZF1 IKZF3
CUL4A
DDB1 ROC
E2 Ub
Ub Ub Ub Ub
CRBN
IKZF1 and IKZF3 proteasomal degradation