Lecture 7 - Immune Therapy

Question 1

Origins of modern cancer immunotherapy

Answer 1

coley’s toxin - promotes non-specific inflammatory response in hopes of activating immune system to kill cancer cells

Question 2

Innate immunity

Answer 2

not programmed

Question 3

Adaptive immunity

Answer 3

programmed B and T cells

Question 4

B cells

Answer 4

antibody producing cells

Question 5

Antibodies

Answer 5

the humoral arm of the immune system
the variable domain is what binds to the antigen

Question 6

Humanization of antibodies

Answer 6

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)

Question 7

Nomenclature and monoclonal antibodies

Answer 7

mouse = -o
chimeric (one mouse one human) = -xi
humanized = -zu
fully human = -u

Question 8

Antibody binding alone can lead to several anticancer events

Answer 8

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

Question 9

Trastuzumab (herceptin)

Answer 9

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

Question 10

Trastuzumab toxicities

Answer 10

flu-like sx, risk of cardiomyopathy, risk of hypersensitivity rxns

Question 11

Pertuzumab

Answer 11

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

Question 12

Differential binding of trastuzumab vs pertuzumab

Answer 12

both bind to HER2 but in different regions

Question 13

Margetuximab

Answer 13

slightly better survival in pretreated pts compared to trastuzumab

Question 14

Cetuximab

Answer 14

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

Question 15

Cetuximab toxicities

Answer 15

severe infusion reaction
acneiform rash! - indicative of better prognosis
asthenias
fever

Question 16

Panitumumab

Answer 16

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

Question 17

Panitumumab SEs

Answer 17

skin rash
diarrhea
does not carry infusion toxicities

Question 18

Bevacizumab

Answer 18

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

Question 19

Targeting CD20 in B-cell lymphoma

Answer 19

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

Question 20

Rituximab

Answer 20

binds to CD20
CD20 is expressed by normal B lympocytes and immature pre-B cells and B-cell non-hodgkin’s lymphoma cells

Question 21

Ofatumumab

Answer 21

full human monoclonal antibody specific for CD20
for B-cell lymphomas (non-Hodgkin’s lymphoma)

Question 22

Daratumumab

Answer 22

CD38 is multifunctional transmembrane protein highly expressed on plasma B cells that make antibodies
antibodies for CD38 eliminate multiple myeloma cells

Question 23

Antibody drug conjugates - ado-trastuzumab emtansine

Answer 23

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

Question 24

Trastuzumab emtansine toxicity

Answer 24

AEs of trastuzumab
thrombocytopenia
hepatotoxicity

Question 25

Trastuzumab-deruxtecan

Answer 25

TOPOI inhibitor

Question 26

Major issues for T cell-based immunotherapy

Answer 26

central tolerance: repertoire to self is irrevocably compromised
immunosuppression/peripheral tolerance

Question 27

Tolerance of T-cells to avoid autoimmunity

Answer 27

central tolerance
peripheral tolerance

Question 28

Central tolerance

Answer 28

negative selection of T-cells that bind to self peptides in thymus

Question 29

Peripheral tolerance

Answer 29

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

Question 30

Central T-cell tolerance

Answer 30

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

Question 31

T-cell activation

Answer 31

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)

Question 32

Overcoming central tolerance

Answer 32

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

Question 33

Combination therapies are needed to

Answer 33

address multiple steps in the immune process to implement immunotherapy

Question 34

Steering wheel

Answer 34

T cell recognition - get T cell to recognize cancer cell

Question 35

Bispecific T-cell engager (BiTE)

Answer 35

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

Question 36

Blinatumomab

Answer 36

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

Question 37

Mosunetuzumab

Answer 37

BiTE that targets CD3 and CD20 on non-hodgkin lymphomas
SE: cytokine release syndrome when immune system responds too aggressively

Question 38

Teclistamab

Answer 38

BiTE that targets CD3 on T cells and B-cell maturation antigen (BCMA) on myeloma cells

Question 39

Taquetamab

Answer 39

BiTE that targets CD3 on T cells and human G-protein coupled receptor family C group 5 member D (GPRC5D) on myeloma cells

Question 40

Remove suppression

Answer 40

“remove emergency brake” that comes from peripheral tolernace

Question 41

CTLA-4 and PD1 act as

Answer 41

brakes or checkpoints on the immune system
blocking these interactions with antibodies can reactivate T-cells

Question 42

Ipilimumab

Answer 42

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

Question 43

Pembrolizumab

Answer 43

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

Question 44

Atezolizumab

Answer 44

monoclonal antibody that binds program death-ligand 1 (PD-L1) receptor and blocks its interaction with PD-1