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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!