Lecture 7 - Immune Therapy Flashcards
Origins of modern cancer immunotherapy
coley’s toxin - promotes non-specific inflammatory response in hopes of activating immune system to kill cancer cells
Innate immunity
not programmed
Adaptive immunity
programmed B and T cells
B cells
antibody producing cells
Antibodies
the humoral arm of the immune system
the variable domain is what binds to the antigen
Humanization of antibodies
antibodies produced in mice need to be changed to mimic a human protein or they’ll be recognized as foreign by the patient’s immune system
using molecular biology and protein expression one can construct a cell line that secretes antibodies that are mostly human except for the complementarity determining region (from mouse)
Nomenclature and monoclonal antibodies
mouse = -o
chimeric (one mouse one human) = -xi
humanized = -zu
fully human = -u
Antibody binding alone can lead to several anticancer events
binding of antibodies to cell surface receptors often times will inhibit their function
binding of several antibodies to a receptor on the surface of cancer cell can lead to complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) and selection elimination of tumor cell by immune system
Trastuzumab (herceptin)
recombinant humanized monoclonal antibody specific to HER2
contains receptor binding domain of mouse monoclonal antibody linked to human IgG kappa framework, this framework reduces immune response to the antibody
herceptin binds to receptor and induces antibody-dependent cellular cytotoxicity and receptor internalization and degradation
indicated for breast cancer that overexpresses HER2
Trastuzumab toxicities
flu-like sx, risk of cardiomyopathy, risk of hypersensitivity rxns
Pertuzumab
recombinant humanized monoclonal antibody specific for HER2
HER2 dimerization is an important element of optimal HER2 response, pertuzumab binds HER2 and inhibits dimerization
use in combo with trastuzumab - increases efficacy
Differential binding of trastuzumab vs pertuzumab
both bind to HER2 but in different regions
Margetuximab
slightly better survival in pretreated pts compared to trastuzumab
Cetuximab
recombinant chimeric monoclonal antibody that binds specifically to extracellular domain of EGF receptor - competitively inhibits binding of EGF and TGF-alpha
blocks phosphorylation and activation of receptor-associated kinases –> leads to inhibition of cell growth and induction of apoptosis
EGF receptor is over-expressed in cancers
primary indication is in colorectal and head and neck cancers
Cetuximab toxicities
severe infusion reaction
acneiform rash! - indicative of better prognosis
asthenias
fever
Panitumumab
fully humanized monoclonal antibody that binds specifically to extracellular domain of EGF receptor (less of an immune rxn to antibodies)
competitively inhibits binding of EGF and TGF-alpha, blocks phosphorylation and activation of receptor-associated kinases, leads to inhibition of cell growth and induction of apoptosis
indicated in colorectal cancer
Panitumumab SEs
skin rash
diarrhea
does not carry infusion toxicities
Bevacizumab
recombinant humanized monoclonal antibody specific for vascular endothelial growth factor (VEGF)
binds to VEGF and blocks interaction with endothelial receptors, blocks endothelial cell proliferation and new blood vessel formation, inhibits solid tumor growth via anti-angiogenic effect
NO evidence of efficacy as single agent
used in combo with 5-FU in colorectal cancer; bevacizumab binds ligand, ramucirumab binds receptor
Targeting CD20 in B-cell lymphoma
CD20 works with B-cell receptor to drive proliferation of B-cells, also plays role in proliferation of B-cell lymphomas
antibody binding to CD20 inhibits B cell proliferation and induces antibody dependent cytotoxicity
Rituximab
binds to CD20
CD20 is expressed by normal B lympocytes and immature pre-B cells and B-cell non-hodgkin’s lymphoma cells
Ofatumumab
full human monoclonal antibody specific for CD20
for B-cell lymphomas (non-Hodgkin’s lymphoma)
Daratumumab
CD38 is multifunctional transmembrane protein highly expressed on plasma B cells that make antibodies
antibodies for CD38 eliminate multiple myeloma cells
Antibody drug conjugates - ado-trastuzumab emtansine
antibody-drug conjugate consisting of cytotoxic agent emtansine linked to monoclonal antibody trastuzumab
trastuzumab binds to HER2/Neu receptor and leads to usual herceptin response, emtansine enters cells and inhibits microtububle assembly
emtansine toxicity significantly reduced because of selective HER2 targeting
for HER2 positive metastatic breast cancer
Trastuzumab emtansine toxicity
AEs of trastuzumab
thrombocytopenia
hepatotoxicity
Trastuzumab-deruxtecan
TOPOI inhibitor
Major issues for T cell-based immunotherapy
central tolerance: repertoire to self is irrevocably compromised
immunosuppression/peripheral tolerance
Tolerance of T-cells to avoid autoimmunity
central tolerance
peripheral tolerance
Central tolerance
negative selection of T-cells that bind to self peptides in thymus
Peripheral tolerance
self reactive T cells that escape the thymus into peripheral tissues are unactivated to an unresponsive state by Tregs or fail to be properly stimulated by APCs
Central T-cell tolerance
non-selection: binds too weakly, T cells not activated to go out –> apoptosis
positive selection: binds just righ, released from thymus and goes to peripheral –> survival of T-cells
negative selection: binds too tightly –> apoptosis
T-cell activation
requires antigens to be presented to them by membrane-bound MHC
naive T-cell encounters antigen in combo with MHC –> if T-cell receptor recognizes antigen, it will become activated –> cytolytic T-cell will kill that cell and proliferate creating a pop of antigen specific T-cells –> once infection (tumor) is cleared, those T-cell pop will die down to a memory pop to combat that antigen again (long term immunity)
Overcoming central tolerance
redirect T cells to cancer using genetic means
redirect T cells to cancer using recombinant proteins
lower the threshold to allow for targeting neo-antigens
Combination therapies are needed to
address multiple steps in the immune process to implement immunotherapy
Steering wheel
T cell recognition - get T cell to recognize cancer cell
Bispecific T-cell engager (BiTE)
antibody designed to bring T cell to cancer; only works if you have an antigen to bind to and need good cell surface marker
binds simultaneously to CD19 on B cell lymphomas and CD3, which is present on all T cells
Blinatumomab
first BiTE that target T cells to receptors highly expressed on cancers
binds CD3 to physically bring an activated T-cell into proximity with CD19, which is highly expressed on B cells and leukemia; the activated T-cell than lyses the tumor cell
Mosunetuzumab
BiTE that targets CD3 and CD20 on non-hodgkin lymphomas
SE: cytokine release syndrome when immune system responds too aggressively
Teclistamab
BiTE that targets CD3 on T cells and B-cell maturation antigen (BCMA) on myeloma cells
Taquetamab
BiTE that targets CD3 on T cells and human G-protein coupled receptor family C group 5 member D (GPRC5D) on myeloma cells
Remove suppression
“remove emergency brake” that comes from peripheral tolernace
CTLA-4 and PD1 act as
brakes or checkpoints on the immune system
blocking these interactions with antibodies can reactivate T-cells
Ipilimumab
recombinant human monoclonal antibody with unique MOA - cytotoxic T lymphocytes have capacity to recognize and destroy malignant tumor cells, tumor cell antigens recognized by dendritic cells, which present the antigens to CTLs, dendritic cells also deliver inhibitory signal to CTLs via CTLA-4 receptor
ipilumumab binds to CTLA-4 receptor and reverses CTL inhibition
approved for melanoma
severe immune-mediated AEs
Pembrolizumab
monoclonal antibody that binds program death-1 (PD-1) receptor and blocks its interaction with PD-ligand 1 and 2 (PD-L1 and PD-L2)
PD-1 is expresed on T cells
PD-L1 is expressed on macrophages and tumor cells
blocking PD-1 prevents inhibitory signaling within T-cells, leading to enhanced tumor cell killing
approved for melanoma and NSCLC is tumor positive for PD-L1
Atezolizumab
monoclonal antibody that binds program death-ligand 1 (PD-L1) receptor and blocks its interaction with PD-1
