Bases for Immunotherapy in Multiple Myeloma

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1 Bases for Immunotherapy in Multiple Myeloma Paola Neri, MD, PhD Associate Professor of Medicine University of Calgary, Arnie Charbonneau Cancer Institute

2 Disclosures Paola Neri MD, PhD Grants/research support: MMRF, CIHR, LLS Speakers bureau/honoraria: Bristol Myers Squibb, Celgene, Janssen, Takeda Consulting fees: Celgene, Janssen, Takeda

3 Outline 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

4 Components of Myeloma Milieu There is an intimate relationship between PC and BM milieu where PC are hosted in special niches and receive multiple signals that 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

5 The Myeloma Niche 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. Teru Hideshima et al, Nature Reviews 2007

6 Mechanisms of Tumor Escape in Myeloma MM evolution is known to be associated with progressive immune dysregulation and loss of immune surveillance that fosters disease progression, drug resistance and facilitate immune escape. Th1 Dendritic cells CD80/ CD86 IL 6 CD28 Malignant Plasma cells IL 2 IFN IL 10 IL 4 Th2 IDO TGF IL 6 Th17 Naïve CD4+ T cells Bone Marrow Stromal Cells IL 17 RANKL Tcells Treg cells CTLs OCs 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). Brown RD et al, Blood 2001 Brimness MK et al, Clin Exp Immunol 2006 Leone P et al, Blood 2015 Nair JR et al, Oncoimmunology 2012 Ogawara H et al, Leuk Res 2005 Korn T et al, PNAS 2008 Prabhala R et al, Blood 2010 Noonan K et al, Blood 2010

7 T cells Myeloid cells Mechanisms of Tumor Escape in Myeloma Malignant Plasma cells Macrophages M2 Tumor growth Arg 1 NOS MDSCs ROS Bone Marrow Stromal Cells CXCR4 CXCL12 IL 10 IL 1 TNF VEGF IL 8 FGF 2 CSF 1 Invasion IL 6 IL 10 IL 18 Plasmacytoid DCs T cells M2 Treg cells T cells IL 10, VEGF IL 8, IL 15 IL 6, SDF1 a Tumor growth, chemotaxis and drug resistance Nakamura K et al, Cancer Cell 2018 Gabrilovich DI et al, Nat Rev Immunol 2009 Gorgun GT et al, Blood 2013 Rodriguez PC et al, Cancer Res 2004 Malek E et al, Blood Rev 2016 Biswas SK, Nat Immunol 2010 Shay G et al, J Mol Med 2016 Lande R et al, Ann NY Acad Sci 2010 Chauhan D et al, Cancer Cell 2009

8 Mechanisms of Tumor Escape in Myeloma Malignant Plasma cells Recruitment of immunosuppressive cells (T regs, MDSCs, pdcs) Reduced expression of tumor antigens Upregulation of surface (WT1, Muc1) inhibitory ligands (PD L1, LAG3, TACI) Reduced expression of HLA costimulatory molecules (CD40, CD80) Lower expression of HLA DR Shed MHC class I chain related protein A (MICA) Induce Tumor escape Inadequate T cell stimulation and Impaired cytotoxicity Mediate T cell anergy/exhaustion Brown RD et al, Leuk Lymphoma 1998 Jinushi M et al, PNAS 2008 Paiva B et al, Leukemia 2015 Iwai Y et al, PNAS 2002

9 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 1996 Bellucci R et al, Blood 2004 Myeloma Trialists Collaborative groups, Br J Haematol 2001

10 Immunotherapeutic strategies in development in MM 1) Agents that reverse tumor mediated immune paralysis Immunomodulatory drugs Immune Checkpoint Inhibitors 2) Agents that selectively target the malignant clone Monoclonal Antibodies 3) Agents that activate immune cells to target the tumor Chimeric Antigen Receptor (CAR) T cells/ Bites Dendritic cell or peptide Vaccine Adjuvant Therapy Immune Booster Connecting Flights Passive Immunity Targeting a receptor Truly Targeted Therapy Active Therapy Delivering Cells Risk Off Target effects Neri P et al, Clinical Cancer Res 2016

11 CUL4A ROC DDB1 E2 Ub CRBN IKZF1 Ub IKZF3 Ub Ub Ub IKZF1 and IKZF3 proteasomal degradation 1. Kronke J et al. Science Lu G et al. Science Neri P et al Blood 2015 IMIDs hyper/neomorphe the CUL4a CRBN E3 ligase to promote the proteasomal degradation of Ikaros and Aiolos releasing IKZF1 transcriptional regression of IL 2 and type I/II interferon response genes