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Emerging Concepts in Immuno-Oncology: CAR-Ts and BiTEs Rob Laister PhD. Princess Margaret Cancer Centre Hallmarks of Cancer in the year 2000 Hanahan and Weinberg, 2000, Cell, 2, 57-70 Hallmarks of Cancer -Immune Evasion has Emerged as a Hallmark of Cancer Hanahan and Weinberg, 2011, Cell, 2, 647-674 Hallmarks of Cancer -Immune Evasion has Emerged as a Hallmark of Cancer Hanahan and Weinberg, 2011, Cell, 2, 647-674 -What counter measures can we take to prevent Immune Evasion and how can we translate this into patient care ? Immuno-Oncology in Canada: a piece of science history - Ernest McCulloch describes the concept of a hematopoetic stem cell -the first allogenic stem cell transplant using a twin as a donor was performed at the Princess Margaret Hospital in 1972 ) What is Immuno-Oncology? Classical Immuno-Oncology -stem cell transplants -cytokine therapies -standard antibody mediated therapies Next Generation Immuno-Oncology Strategies - CAR T-cell technology - BiTEs -Overcoming Immune Checkpoints - Antibody drug conjugates -Immunomodulatory drugs/Imids -Oncolytic viruses -Cancer vaccines -Immunokinase inhibitors Chimeric Antigen Receptor (CAR) T-cell Technology Chimeric Antigen Receptor (CAR) T-cell Technology Chimeric Antigen Receptor (CAR) T-cell Technology Chimeric Antigen Receptor (CAR) T-cell Technology -how do you engineer a T-cell ? Chimeric Antigen Receptor (CAR) T-cell Technology Antigen recognition (ex anti-CD19 for B-cells) CD3: T-cell activation and cytotoxicity -antigen selection drives specificity for target cell -want to select antigen that is expressed on cancer cells but not on healthy tissue Chimeric Antigen Receptor (CAR) T-cell Technology 1st generation Antigen recognition (ex anti-CD19 for B-cells) CD3: T-cell activation and cytotoxicity -Cells not long lived and do not proliferate Chimeric Antigen Receptor (CAR) T-cell Technology Base model Chimeric Antigen Receptor (CAR) T-cell Technology Base model A little fancier Chimeric Antigen Receptor (CAR) T-cell Technology Base model A little fancier Top Gear Chimeric Antigen Receptor (CAR) T-cell Technology 1st generation anti-CD19 CD3 -Cells not long lived and do not proliferate Chimeric Antigen Receptor (CAR) T-cell Technology 1st generation 2nd generation anti-CD19 CD28 CD3 -addition of the endodomain of CD28 co-stimulatory molecule increases in vivo persistence by activating the PI3K-AKT-mTOR pathway leading to proliferation and protein synthesis. Chimeric Antigen Receptor (CAR) T-cell Technology 1st generation 2nd generation 3rd generation anti-CD19 4-1BB CD28 CD3 -addition of a fragment of 4-1BB enhances survival by activation of NFKB. Chimeric Antigen Receptor (CAR) T-cell Technology 1st generation 2nd generation 3rd generation anti-CD19 4-1BB (NFKB) CD28 (PI3K) CD3 (TCR) Cytotoxicity Proliferation Survival Armoured CAR-Ts 3rd generation anti-CD19 4-1BB -armoured CAR T-cells are engineered to secrete IL-12 to protect from regulatory T-cell mediated inhibition CD28 CD3 Cytotoxicity Proliferation Survival IL-12 Armoured CAR-Ts 3rd generation anti-CD19 4-1BB …could there be issues with making a super killing machine that can’t be destroyed ?? CD28 CD3 Cytotoxicity Proliferation Survival IL-12 Rise of the Immunomachines? Chimeric Antigen Receptor (CAR) T-cell Technology 3rd generation CD20 Express cell Surface CD20 to remove with Rituximab anti-CD19 4-1BB CD28 CD3 IL-12 Inducible Cell Death Modules 3rd generation IL-12 Inducible caspase9 Drug binding domain Inducible Cell Death Modules 3rd generation Small molecule inducer of dimerization (oral administration) Inducible caspase9 (inactive monomer) Drug binding domain IL-12 Inducible Cell Death Modules 3rd generation IL-12 Activated caspase9 dimer Cell Death Chimeric Antigen Receptor (CAR) T-cell Technology CD20 anti-CD19 4-1BB Inducible caspase9 CD28 CD3 IL-12 CAR T-cells in Clinical Trials Target Antigens in Heme CD19: CLL/NHL/ALL CD20: NHL Lewis Y: AML (tetrasaccharide) Kershaw, et al., 2013, Nat Rev Can, 13, 525-541 Bispecific T-Cell Engagers: BiTes Antigen recognition -binds to tumour cell Immune effector recruitment -binds to T-cell binding Bispecific T-Cell Engagers: BiTes Antigen recognition Tumour cell cytotoxins T-cell binding (CD16) T-cell Bispecific T-Cell Engagers: BiTEs CD3 Monoclonal antibody -binds to T-cells Monoclonal antibody against tumour antigen -binds to cancer cell Bispecific T-Cell Engagers: BiTEs Fragment that binds to T-cells Fragment that bind to tumour cell Bispecific T-Cell Engagers: BiTEs Fragment that binds to T-cells Linker Fragment that bind to tumour cell Bispecific T-Cell Engagers: BiTEs Tumour cell Bispecific T-Cell Engagers: BiTEs Tumour cell Cytotoxins Immune synapse T-cell Bispecific T-Cell Engagers: BiTEs Tumour cell Cytotoxins Immune synapse T-cell BiTEs have been shown to cause cytokine storms, perhaps due to enhanced numbers of or through the artificial creation of the Immune synapse Bispecific T-Cell Engagers: BiTEs Dendritic Cell Tumour cell MSC NK-cell T-cell Can you orchestrate the players recruited Into the tumour microenvironment ? Hallmarks of Cancer : Immuno-metabolism Hanahan and Weinberg, 2011, Cell, 2, 647-674 Cancer Immuno-metabolism Chang, et al., 2015, Cell, 162, 1229-1241 -Cancer cells have greatly elevated metabolic rates (FDG-PET) that enable them to outcompete T-cells for nutrients in the tumour microenvironment. Cancer Immuno-metabolism Sukumar, et al., 2015, Cell, 162, 1206-1208 -Cancer cells have greatly elevated metabolic rates (FDG-PET) that enable them to outcompete T-cells for nutrients in the tumour microenvironment. Cancer Immuno-metabolism: checkpoint blockade Sukumar, et al., 2015, Cell, 162, 1206-1208 -antibodies targeting PD-L1 on the surface of tumour cells inhibits glucose uptake. -anti-PD-L1s may be beneficial to T-cell function beyond checkpoint blockade Thank You Enjoy Toronto and CHC 2015!