Oncology Immunotherapy - Dr. Wendt Flashcards
(118 cards)
1
Q
Name a drug that targets HER2
A
Tucatinib
2
Q
Name a drug that targets a kinase that is produced by formation of the Philadelphia chromosome
A
Imatinib (exam question)
3
Q
Name a compound that is not a covalent kinase inhibitor
A
Gefitinib
4
Q
What TYPE of kinase inhibitor can bind in the ATP sight and stabilize the inactive conformation of a kinase
A
Type II
5
Q
Name a drug that prevents the phosphorylation of lipids
A
Alpelesib
6
Q
Describe how the T315I prevents the binding of imatinib to BCR-Abl
A
The T315I mutation prevents the binding of imatinib to BCR-Abl
7
Q
What might the next course of BCR-Abl-targeted therapy might include?
A
Ponatinib is indicated upon identification of the T315I mutation
8
Q
What is Coley’s toxin?
A
aka MBV (mixed bacterial vaccine) was the first attempt to use immunotherapy and hyperthermia against cancer.
William B. Coley MD was a bone surgeon at MSK from 1893 - 1936 and developed an interest when his first patient, a young girl, died from metastatic sarcoma
9
Q
In 1953 ______ pharmaceutical companies were producing different versions of ____________
A
two; Coley’s toxin
10
Q
___________ has changed the face of cancer therapy
A
T-cell targeting
11
Q
Define positive selection
A
permits the survival of only those T cells whose TCRs are capable of recognizing self-MHC molecules.
It is responsible for the creation of a self-MHC-restricted repertoire of T cells
cells that fail positive selection are eliminated within the thymus by apoptosis
12
Q
Define negative selection
A
eliminates T cells that react too strongly with self-MHC or with self-MHC plus self-peptides
bearing high-affinity receptors for self-MHC molecules alone or self-antigen presented by self-MHC, which results in self-tolerance
it is an extremely important factor in generating a primary T-cell repertoire that is self-tolerant
13
Q
T-cells arise in the bone marrow BUT migrate to the ________ for maturation
A
thymus
14
Q
T-cells don’t recognize antigen alone, but recognize antigen (small peptides) presented to them by _______________
A
cell-membrane bound MHC
15
Q
Name types of T-cells
A
- helper T-cells – CD4
- cytolytic T-cells – CD8
- Regulatory T-cells
16
Q
What are the steps of T-cell function
A
a naïve T-cell encounters presented antigen in combination with MHC
If the T-cell receptor (TCR) recognizes the antigen it will become activated. A cytolytic T-cell will kill that cell and proliferate creating a population of antigen specific T-cells
Once an infection (tumor) is cleared those T-cell population will die down to a memory population well suited to combat that antigen again (immunity)
17
Q
Antibody production: the __________ of the immune system
A
humoral arm
18
Q
Describe “humanization” of antibodies
A
- Antibodies produced in mice need to be changed to mimic a human protein or they will be recognized by the the patients immune system.
- Using molecular biology and protein expression one can construct a cell line, that secretes antibodies that are mostly human, except for complementarity determining region (CDR); Humanized
- There are transgenic mice that have been constructed to express the human VDJ regions of the genome so they produce fully human antibodies.
19
Q
Stem of all monoclonal antibodies is _____
A
-mab
20
Q
substem that indicates mouse
A
-o
21
Q
substem that indicates chimeric
A
-xi
22
Q
substem that indicates humanized
A
-zu
23
Q
substem that indicates fully human
A
-u
24
Q
Antibody binding can lead to several _________ events
A
anticancer
25
binding of large protein complexes such as antibodies to cell surface receptor often times will _________ their function
inhibit
26
Just as is the case with the normal immune course, binding of several antibodies to a receptor on the surface of a cancer cell can lead to __________-__________ ________________ and _______________-______________ ______________ _________________ (ADCC) and_____________ _______________ of the tumor cell by the immune system
complement-dependent cytotoxicity; anti-body-dependent cellular cytotoxicity (ADCC); selective elimination
27
This ____________ affect may be why blocking antibodies have unique effects over _____________
two tiered; kinase inhibitors
28
HER2 is also...
...p185
29
______ is genetically amplified in ____________
HER2; breast cancer
30
Trastuzumab brand
Herceptin
31
What is trastuzumab?
Recombinant humanized monoclonal antibody specific for HER2
Contains receptor binding domain of mouse monoclonal antibody linked to a human IgG1 kappa framework
This human framework reduces the immune response to the antibody
32
HER2 is overexpressed in ____________ of all breast cancers
25-30%
33
Herceptin binds to receptor and induces __________-__________ ____________ ___________. It also induces receptor ______________ and _______________
antibody-dependent cellular toxicity; internalization; degradation
34
Primary indication of Herceptin...
...is in the treatment of breast cancers that overexpress HER2
35
Toxicities of Herceptin
Flu-like symptoms (fever, chills, nausea, vomiting, myalgias)
Risk of cardiomyopathy/CHF – increased in combination with Adriamycin
No intrinsic myelosuppression but increases in combination with chemotherapy
Risk of hypersensitivity reactions (“foreign” protein)
36
Pertuzumab brand
Perjeta
37
What is Pertuzumab
Recombinant humanized monoclonal antibody specific for HER2
HER2 dimerization is an important element of optimal HER2 response
Pertuzumab binds to HER2 and inhibits dimerization
Used in combination with trastuzumab
38
What drug involved the CLEOPATRA trial
pertuzumab
39
What happened during the CLEOPATRA trial?
Pertuzumab+Trastuzumab+Docetaxel vs. Placebo+Trastuzumab+Docetaxel
Progression-free survival increased 6 months (18.5 vs. 12.4 months)
No significant differences in safety profile
Taxane;Herceptin;Perjeta (THP) combination therapy is now 1st line standard of care.
40
Can the pertuzumab/trastuzumab combo product be used at home?
No
41
Trastuzumab binds at the _____ location
IV
42
Pertuzumab binds at the _____ location
II
43
__ engineering can improve immune activation by therapeutic antibodies
Fc
44
________________ showed slightly better survival in pretreated patients as compared to ________________
Margetuximab; trastuzumab (SOPHIA trial)
45
Cetuximab brand
Erbitux
46
What is Cetuximab?
Recombinant chimeric monoclonal antibody that binds specifically to the extracellular domain of the 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
47
EGF receptor is constitutively expressed in many normal epithelial tissues. Receptor is overexpressed in many ______ ___________
human cancers
48
Primary indication of Cetuximab...
...is in the treatment of colorectal and head and neck cancers
49
Toxicities of Cetuximab
WARNING! Severe infusion reaction in ~ 3% of patients – usually 1st dose:
- Acneiform rash
- Asthenias
- Fever
50
The ________ ____ is associated with ____________. Occurence of the rash is __________ associated with disease response.
anciform; EGFR-inhibition; positively
51
Panitumumab brand
Vectibix
52
What is panitumumab?
Fully humanized monoclonal antibody that binds specifically to the extracellular domain of the 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
53
How often is panitumumab given?
every 2 weeks
54
SE of panitumumab
Skin rash and other cutaneous side effects (this predictive of better clinical outcome)
Diarrhea
55
Primary indication of panitumumab...
...is in the treatment of colorectal cancer
56
Panitumumab does not carry any ______________
infusion toxicities
57
Name an antibody that targets HER2
Pertuzumab
58
Explain the two-tiered targeting affect of antibody therapy as compared to small molecule kinase inhibitors
In general antibodies bindings to their targets on the surface of tumor cells will inhibit the function of that molecule. This along with activation of the ADCC can lead to differential therapeutic outcomes when using antibodies as compared to the small molecules.
59
What was the first immunotherapy?
Coley's toxin
60
Describe why the combined use pertuzumab and trastuzumab both defies and complies with general rules of combination therapy?
Against: Shared target equals shared toxicities.
For: Different bindings sites on HER2, different mechanisms of HER2 inhibition, enhanced activation of the ADCC.
61
Signaling pathways are __________ events. In fact, administration of cetuximab and panitumumab for the treatment of __________ _________ _______now requires ______ ______________ status
sequential; metastatic colorectal cancer; KRAS mutational
62
CD20 works with the _-____ ________ to drive the proliferation of __-_____
B-cell receptor (BCR); B-cells
63
CD20 also plays a role in the proliferation of _-____ _____________
B-cell lymphoma
64
Ofatumumab is a...
...fully human monoclonal antibody specific for CD20
65
Ofatumumab is a ____________ protein that regulates an early step in activation of cell cycle ____________ and _______________
transmembrane; initiation; differentiation
66
CD20 is expressed by normal __ __________________ and ____________ ___-__ _____. It is also expressed on > 90% of B-cell ___-__________ ______________ _____
B lymphocytes; immature pre-B cells; non-Hodgkin's lymphoma cells
67
Primary indication of Ofatumumab...
...is in treatment of B-cell non-Hodgkin's lymphoma
68
Several other _______ antibodies are currently approved for B-cell lymphomas, some of them have different ____________ _______ on CD20 (Cetuximab, Obinutuzumab). Numerous antibodies entering the market to target various cell surface makers for the treatment of __________ and _________ malignancies
CD20; binding sites; Lymphoid; Myeloid
69
Bevacizumab brand
Avastin
70
What is Bevacizumab?
Recombinant humanized monoclonal antibody specific for vascular endothelial growth factor (VEGF)
Binds to VEGF and blocks its interaction with endothelial receptors
Blocks endothelial cell proliferation and new blood vessel formation
Inhibits solid tumor growth via anti-angiogenic effect
71
For Bevacizumab, there is...
...no evidence of efficacy as a single agent
72
Bevacizumab indication
used in combination with 5-FU based chemotherapy for first-line treatment of metastatic colorectal cancer
73
Bevacizumab binds the ______, Ramucirumab binds the ________. There are an array of small molecules that inhibit the kinase activity.
ligand; receptor
74
What does ADC stand for?
Antibody Drug Conjugates
75
Trastuzumab Emtansine brand
Kadcyla
76
What is Trastuzumab?
TDM1 is an antibody-drug conjugate consisting of the cytoxic agent linked to the monoclonal antibody trastuzumab
Trastuzumab binds to HER2/Neu receptor and leads to usual herceptin response
Emtansine enters cells and inhibits microtubule assembly
Emtansine toxicity significantly reduced because of HER2 targeting
77
Trastuzumab indication
approved as second line treatment for HER2-positive metastatic breast cancer
78
Additional drugs being conjugated to trastuzumab...
...is trastuzumab-deruxtecan. The "tecans" are TOPOI inhibitors
79
Trastuzumab toxicites
Adverse effects of trastuzumab (as expected)
Thrombocytopenia (mertansine effect)
Hepatotoxicity (mertansine effect)
80
Lymphomas arise from cells that populate ________ ______
lymph nodes
81
Brentuximab vedotin brand
Adcetris
82
What is brentuximab vedotin?
An anti-CD30 anitbody conjugated to Monomethyl auristatin E (MMAE)
Reed-Sternberg cells express CD30
MMAE is a microtubule destabilizing agent, ~200 times more potent than vinblastine.
MMAE is so toxic it cannot be used by itself, conjugation to the antibody targets the compound to the lymphoma cells.
83
The major goal and challenge of cancer immunotherapy is to...
..direct the immune system to recognize and destroy cancer
84
At the point where the tumor is established, natural balance has fundamentally ___________ against the ability to mount an effective ________ _________
shifted; immune response
85
What are the major issues (2) for T-cell based immunotherapy?
- central tolerance: repertoire to self is irrevocably compromised
- immunosuppression/peripheral tolerance
86
What percentage of T-cells are deleted?
98%
87
What does central tolerance entail?
The potent repertoire to self antigens has been deleted --> clonal elimination in thymus of all high avidity self reactive T cells
Redirect T cells by genetic means
Redirect T cells using recombinant proteins
Develop neo-antigen-targeting strategies
"Empower" T cells that recognize non-self in cancer (relieve peripheral tolerance to non-self reactive T cells)
88
_________ ______________ points are likely to be required for maximally effective implementation of immunotherapy
Multiple Intervention
89
Established tumors have developed a breadth of mechanisms to counterbalance anti-tumor immunity: ____________ ___________ needed to address multiple steps in the immune process
Combination therapies
90
Interleukin-2 brands
Proleukin + Aldesleukin
91
What is interleukin?
recombinant protein
IL-2 is a lymphokine produced by activated T cells
Variety of actions – primary is the ability to stimulate proliferation of activated T cells bearing IL-2 receptors
Enhances lymphocyte mitogenesis and cytotoxicity
Also activates Natural Killer cells activity
In vivo administration produces multiple immunologic effects
Highly pro-inflammatory cytokine
92
Interleukin indications
variety
93
T or F: Interleukin is extremely nonspecific
TRUE
94
Interleukin toxicities
fever
malaise
fatigue
anorexia
95
__________ intervention points are likely to be required for __________ effective implementation of immunotherapy
multiple; maximally
96
Established tumors have developed a breadth of mechanisms to _______________ anti-tumor immunity: ______________ therapies needed to address multiple steps in the immune process
counterbalance; combination
97
CLTA-4 and PD1 act as _________ or _____________ on the immune system. Blocking these interactions with antibodies keeps T-cells ____________
brakes; checkpoint; activated
98
Ipilimumab brand
Yervoy
99
What is ipilimumab
Recombinant human monoclonal antibody with a unique mechanism of action
Cytotoxic T lymphocytes (CTLs) have the capacity to recognize and destroy malignant tumor cells
Tumor cell antigens recognized by dendritic cells, which present the antigens to the CTLs
However, dendritic cells also deliver an inhibitory signal to CTLs via the CTLA-4 receptor
Ipilimumab binds to the CTLA-4 receptor and reverses the CTL inhibition
100
T or F: Ipilimumab has a unique mechanism of action
TRUE
101
Ipilimumab indications
approved for treatment of advanced metastatic melanoma
102
Ipilimumab adverse reactions
severe immune-mediated adverse reactions
generally related to inflammatory response:
- GI tract (enterocolitis, hepatitis)
- Dermatitis, neuropathy, endocrinopathy
may require high-dose corticosteroids
103
Pembrolizumab brand
Keytruda
104
Nivolumab brand
Opdivo
105
Cemiplimab brand
Litayo
106
What are pembrolizumab, nivolumab and cemiplimab?
Monocloncal antibodies that bind the program death-1 (PD-1) receptor and blocks its interaction with PD-Ligand 1 and 2 (PD-L1 and PD-L2)
PD-1 is expressed on T-cells
***PD-L1 is expressed on macrophages and tumor cells
Similar to CTLA4 blockade, blockade of PD-1 prevents inhibitory signaling within T-cells leading to enhanced tumor cell killing.
107
pembrolizumab, nivolumab and cemiplimab indications
Approved for the treatment of advanced metastatic melanoma following treatment with Ipilimumab and (if BRAF V600 mutation positive) a BRAF inhibitor.
Also approved for Non-small cell lung cancer if the patients tumor biopsy tests positive for PD-L1.
108
Atezolizumab brand
Tecentriq
109
Avelumab brand
Bavencio
110
Durvalumab brand
Imfinzi
111
What are tezolizumab, avelumab, and durvalumab?
Monocloncal antibodies that bind program death-Ligand 1 (PD-L1) receptor and blocks its interaction with PD-1
PD-1 is expressed on T-cells
PD-L1 is expressed on macrophages and tumor cells
Several indications
112
tezolizumab, avelumab, and durvalumab indications
NSCLC in patients with EGFR or ALK mutations that have progressed on those therapies
indications will continue to grow
113
tezolizumab, avelumab, and durvalumab exclusions
autoimmune disease
medical conditions requiring immunosuppression
114
What is sorafenib?
multi-target kinase inhibitor, hitting RAF, VEGFR, PDGFR and others. Approved in unresectable liver cancer
115
Antitumor immunity can be enhanced by preceding it with ___________
radiation
116
radiation produces ____________
neo-antigens
117
What is BiTE?
Bi-specific T-cell Engager
118
What is Blinatumomab?
Binds to CD19 and CD3
The idea of this bispecific antibody is to physically bring an activated T-cell into proximity with the tumor cell.
The activated T-cell will then lyse the tumor cell.
First of several of these types of antibodies being developed.
Approved for B-cell lymphomas.
***Don’t confuse these with chimeric antibodies.
