immunotherapies Flashcards
REVIEW:
Which of the following is used to describe a cancer derived from pigment producing cells of the eye?
Teratoma
Papilloma
Sarcoma
Melanoma
All of the above
Melanoma
REVIEW
Which of following is NOT a hallmark of cancer?
Resisting cell death
Evading Growth suppressors
Enabling replicative immortality
Activating invasion and metastasis
Increasing in cell size
increasing in cell size
REVIEW
Molecular pathology is different from traditional pathology because…?
-It uses a numerical system to categorize tumor progression.
-It uses some kind of genetic testing to indicate therapy or predict for tumor recurrence.
-It uses stains that allow pathologists visualize nuclear and cytoplasmic size and shape.
-It is not useful when determining a patient’s course of treatment.
-It uses some kind of genetic testing to indicate therapy or predict for tumor recurrence.
REVIEW
Which of the following terms is associated with substitution of tissue type for another?
Hyperplasia
Dysplasia
Metaplasia
Desmoplasia
metaplasia
REVIEW
Which is of the following is an example of a tumor suppressor?
BRCA
HER2
CDK4/6
HPV
BRCA; loss of BRCA results in breast cancers
_________ is sometimes referred to as MBV for _____ _________ _______, and was the first attempt to use immunotherapy & hyperthermia against cancer
Coley’s toxin; mixed bacterial vaccine
t/f Coley’s toxin is FDA approved
false
t/f adaptive immunity involves T cells, B cells & plasma cells
true
which cells of the adaptive immune system produce antibodies (aka antigen presenting cells)
b cells
__________ are the humoral arm of the immune system. what are the two domains that make these up?
antibodies
variable domain & constant domain
we often make antibodies in animals such as, _____. this produces ________ that are then screened for production and cloned into monoclonal antibodies
mice; hydridomas
Antibodies produced in mice need to be changed to mimic a human protein or they will be recognized as foreign by the the__________
Using _________ and _______ one can construct a cell line, that secretes antibodies that are mostly human, except for the ____________ (CDR).
This process can be overcome by constructed transgenic mice to express the human ______ regions of the genome so they produce fully human antibodies
patient’s immune system.
molecular biology and protein expression
complementarity determining region
VDJ
nomenclature & monoclonal antibodies:
what is them of all monoclonal antibodies?
substems:
-mouse =
-chimeric =
-humanized =
-fully human =
-mab
-mouse = o
-chimeric = xi
-humanized = zu
-fully human = u
Binding of large proteins, such as antibodies, to cell surface receptors often times will ___promote/inhibit___their function.
Just as is the case with the normal immune course, binding of several antibodies to a receptor on the surface of cancer cell can lead to ______________ (CDC) and ___________ (ADCC) and selective elimination of the tumor cell by the immune system.
This two-tiered affect may be why blocking antibodies have unique effects over ___________.
inhibit
complement-dependent cytotoxcity
antibody-dependent cellular cytotoxicity
kinase inhibitors
A focus for Mab’s is the ______ family of growth factor receptors
ErbB
t/f HER2 is an oncogene & receptor tyrosine kinase that is genomically amplified in breast cancer
TRUE
based on the substem what is trastuzumab
-mouse
-chimeric
-humanized
-fully human
humanized
Trastuzumab (Herceptin) is a recombinant humanized monoclonal antibody specific for ______
When bound to receptor, herceptin induces what kind of cytoxicity?
>this induces receptor internalization & degradation
HER2
antibody-dependent cellular cytoxicity (ADCC)
HER2 protein is overexpressed in ________% of all breast cancers
25-30%
a pt has breast cancer that is HER2 negative, is trastuzamb (herceptin) a good tx option?
No, herceptin is specific for HER2 and therefore indicated for tx of breast cancers that overexpress HER2
which of the follow are toxicities associated with trastuzumab (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)
> all of the above
> all of the above
SE profile is similar to kinase inhibitors; but hypersensitivity is unique to immunotherapy
Pertuzumab (perjeta) is a recombinant humanized monoclonal antibody specific for _________
HER2
HER2 _______is an important element of optimal HER2 response. When HER2 is increased like in many breast cancers it tends to ________
dimerization; dimerize
Pertuzumab is unique to trastuzumab because while they both bind to HER2, pertuzumab also inhibits ________. This is what it is used in combo with trastuzumab
dimerization of HER2
what trial was used to show efficacy of pertuzumab & trastuzumab combo therapy?
CLEOPATRA
what is the 1st line combo therapy for HER2+ breast cancers
taxane, pertuzumab & trastuzumab
what is an administration limitation of the combo med, Phesgo (pertuzumab & trastuzumab)?
IV only, cannot be used at home
_____ engineering can improve immune activation by therapeutic antibodies. Margetuximab is an example of this (SOPHIA trial).
Fc
Cetuximab is a recombinant __________ monoclonal antibody that binds specifically to the extracellular domain of the _______ receptor
This competively inhibits binding of ______ and _____-alpha
Also blocks phosphorylation & activation of receptor-associated kinases
chimeric; EGF
EGF & TGF-alpha
The primary indication for cetuximab is _________ and _______ cancers
colorectal & head/neck cancers
why is there a warning with cetuximab?
what are 3 other expected toxicities? why are they expected?
~3% of pts have a severe infusion rxn w 1st dose
-acneiform rash
-asthenias (loss of strength)
-fever
EGF inhibition, causes inhibition of EGFR (epidermal growth factor) which is why many SEs are skin related
if pt gets rash it means it’s working
panitumamab is a _______ monoclonal antibody that binds specifically to the extracellular domain of ______ receptor
fully humanized; EGF
what toxicity only occurs with cetuximab & not panitumumab?
infusion toxicity
what are the 2 drugs that competitively inhibit binding of EGF & TGF-alpha?
cetuximab & panitumumab
> similar SE profile
what cancer is indicated for cetuximab & not panitumumab?
head & neck is only cetuximab
both are colorectal
Bevacizumab & Ramucirumab bind to __________. However, _______ binds the ligand & __________ binds the receptor
VEGF; bevacizuman; ramucirumab
t/f there is efficacy of bevacizumab as a single agent for metastaic colorectal cancer
false; must be used as combo
what are VEGF blockers (i.e bevacizumab) used in combo with for 1st line tx of metastatic _______ cancer
5-FU; colorectal
Which of the following antibodies targets Her2?
Neratinib
Cetuximab
Lapatinib
Pertuzumab
Pertuzumab
> cetuximab is EGF receptor target, Neratinib & lapatinib are kinase inhibitors
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 among with activation of the ADCC can lead to differential** see slide
What was the first immunotherapy?
Pertuzumab
Keytruda
Coley’s toxin
Trastuzumab
Coley’s toxin
The antibody Fakeumab has just entered the market. What type of the antibody was it?
Fully human
Humanized
Fully mouse
Chimeric
Fully human
Describe why the combined use pertuzumab and trastuzumab both defies and complies with general rules of combination therapy?
They both target HER2, but there is differential binding so efficacy actually increases
FROM SLIDE:
They target different areas (binding sites) of HER2
Against: Shared target equals shared toxicities
For: diff. bindings sites on HER2, diff. mechanisms of HER2 inhibition, enhanced activation of the ADCC
Results in synergistic response
what is a primary target in B-cell lymphoma?
CD20
CD19
CD22
CD38
CD20
CD20 works with which receptor to drive proliferation of B cells
B-Cell receptor (BCR)
CD20 also plays role in proliferation of B cell lymphomas
_______ binding to CD20 inhibits B cell proliferation and __inhibits/induces___ Antibody-dependent cytotoxicity (ADC)
Antibody binding to CD20 inhibits B cell proliferation and induces Antibody-dependent cytotoxicity
rituximab is a ________ monoclonal antibody
chimeric
what chimeric monoclonal antibody binds to CD20?
rituximab
CD20 is expressed by normal B lymphocytes and __mature/immature__pre-B cells
Also expressed on > __#__% of B-cell non-Hodgkin’s lymphoma cells
immature; 90%
why are rituximab & ofatumumab similar?
both are specific for CD20
ofatumumab is a _________ monoclonal anitbody developed to tx CLL & b-cell lymphomas
fully humanized
t/f CD20 is expressed normally on B cells, not just B cells in lymphoma
true
CD38 is a multifunctional transmembrane protein highly expressed on _____ B cells that make antibodies
Multiple Myeloma is a cancer of malignant ________ cells
plasma
Myeloma; plasma
Daratumumab is a ______ monoclonal antibody that targets _______ that eliminate multiple myeloma cells by ADCC or CDC.
This also eliminates ______ _______cells
fully humanized; CD38
Natural killer (innate immunity)
what monoclonal antibody also eliminates natural killer cells involved in innate immunity?
daratumumab
Trastuzumab Emtansine (TDM1) is a ________-______ conjugate.
Emtansine enters cells & inhibits ________ assembly
what is TDM1 approved to tx?
antibody-drug
microtubule (emtansine is cytotoxic agent)
2nd line tx of HER2+ metastatic breast cancer
emtansine is a modified version of ______, a tubulin inhibitor
mertansine
trastuzumab-deruxtecan is unique because deruxtecan is a ________ inhibitor
TOPO 1 inhibitor
What are the 2 major issues for T cell based immunotherapy?
> central tolerance
immunosuppression/peripheral tolerance
(immune system has already become tolerant to the cancer which is why it’s growing)
match the type of t cell tolerance to avoid autoimmunity with the definition:
Peripheral & Central
> _________tolerance: negative selection of T-cells that bind to ”self” peptides in the thymus.
> _______ tolerance: Self reactive T cells that escape the thymus into peripheral tissues are inactivated to an unresponsive state by Tregs or fail to be properly stimulated by APCs
Central
Peripheral
The T in T cell refers to what?
thymus
In central T-cell tolerance:
non selection & negative selection of T cells leads to ________.
Negative selection refers to if a t cell binds too ___loosely/tightly__.
Non selection refers to tif a t cell binds too ___loosely/tightly__
apoptosis
negative = too tight
non selection = too loose
T cell activation require _______ to be presented to them by membrane bound _____
antigens; MHC
T cell activation steps:
- a naïve T-cell encounters antigen in combination with ____
- If the T-cell receptor (TCR) recognizes the antigen it will become ___inactivated/activated__. A cytolytic T-cell will kill that cell and proliferate creating a population of _______specific T-cells
- Once an infection (tumor) is cleared those T-cell population will die down to a ______population well suited to combat that antigen again (long term immunity)
MHC
activated
antigen
memory
what are the 3 strategies to overcoming central tolerance?
- Redirect T cells to cancer using genetic means (Bispecific T cell engager - BiTE)
- Redirect T cells to cancer using recombinant proteins
- Lower the threshold to allow for targeting neo-antigens
Bispecific T cell engagers (BiTEs) are monoclonal antibodies that have one arm that binds to ____ cell and one that binds to ____ cell that forces binding
T & B cell
t/f BiTEs are chimeric antibodies
FALSE
Blinatumomab is an example of a _____ that target T cells to receptors highly expressed on cancers
BiTEs
BiTE antibodies bind _____ to physically bring an activated ___ cell into proximity with _____, which is highly expressed on B cells & acute lymphoblastic leukemia
CD3; T cell; CD19
what transmembrane protein (CDs) does mosunetuzumab target on non-Hodgkin lymphomas?
CD3 & CD20
cytokine release syndrome is a SE for what drug(s)?
mosunetuzumab (immunotherapies & BiTEs)
> basically When t cells are activated, the immune system is activated which releases cytokines and can lead to cytokine storm
Teclistamab is a BiTE that targets _____ on T cells & b cell maturation antigen (BCMA) on multiple myeloma cells
CD3
what are the 4 BiTEs that we covered?
which two are indicated for multiple myeloma?
blinatumomab
mosunetuzumab
teclistamab -MM
taquetamab -MM
t/f Taquetamab is a BiTE that targets CD3 on T cells and human G-protein coupled receptor family C group 5 member D (GPRC5D) on multiple myeloma cells
TRUE
______ and _______ act as brakes or checkpoints on the immune system
so blocking these interactions w antibodies can reactivate ___ cells
CTLA-4 and PD1
T cells
ipilimumab is a recombinant ___ monoclonal antibody that binds to the _____ receptor & reverses the ____ inhibition
CTLA-4; CTLs (cytotoxic T lymphocytes-able to recognize & destroy malignant tumor cells)
why might ipilimumab require high dose corticosteroids?
severe immune related inflammatory response adverse rxn
>GI tract, dermatitis, neuropathy & endocrinopathy
pembrolizumab (keytruda) binds to _______ receptor and blocks its interactio with ___ ligand 1 & 2
PD-1 & PD
t/f PD-1 is expressed on t cells, while PD-L1 is expressed on macrophages & tumor cells
true
blockade of PD1 prevents inhibitory signaling within t cell leading to enhanced tumor cell killing
Ipilimumab and pembrolizumab treat what kind of cancer
advanced metastatic melanoma
pembrolizumab also for NSCLC if PD-L1+ in biopsy
what must a pt be treated with prior to receiving pembrolizumab (keytruda)
ipilimumab & BRAF inhibitor (if BRAF V600 +)
atezolizumab binds to _____ and blocks interaction with ________
PD-L1 (macrophages/tumor cells); PD-1 (t cells)
sipulcel-T is a therapeutic _______ that contains ___-___-___, an immune cell activator
vaccine; PAP-GM-CSF
what type of cell must be harvested from a pt receiving sipulcel-T (provenge)?
b cell
t cell
APCs
macrophages
Nk cells
what is this process called?
APCs; leukapheresis
t/f after harvesting APCs via leukapheresis for sipulcel-T, they are then activated by in vivo tx with PAP-GM-CSF and then reinfused into pt
false; EX VIVO
t/f The goal of sipulcel-T reinfusion is the stimulate a pt’s own immune system to attack the cancer
true
Sipulcel-T (provenge) is idnicated for what cancer?
metastatic hormone-refractory prostate cancer
t/f the steps of CAR-T cell therapy are as follows:
-remove blood from pt to get T cells
-make CAR T cells in lab
-grow millions of CAR T cells
-infuse CAR T cells into pt
-CAR T cells bind to cancer cells & kill them
TRUE
generally T cell activation is complex and requires activation of multiple proteins, so co-stimulatory receptors are added to a single ______
CAR (chimeric antigen receptor)
> it’s how it gets the “chimeric” part of name
after tx with CAR T cell therapy can pt develop same cancer later in life?
No, lifetime immunity to that cancer, but they can develop other cancers
CD__#__ CAR-T treatments are common and eliminate all immature b cells
19
Which antibody is effective against metastatic melanoma and targets CTLA-4?
Ipilimumab
Trastuzumab
Daratumumab
Blinatumomab
Ipilimumab
Which of the following proteins is used as a cancer biomarker test to determine eligibility for treatment of NSLCL with pemrolizumab?
CD19
CTLA4
PDL1
PD1
PDL1
Which of the following antigens is a common target for CAR-T therapy in B cell malignancy?
A) CD4
B) CD19
C) CD28
D) CTLA4
B) CD19
What is the primary mechanism of action of bispecific T cell engagers in cancer immunotherapy?
A) They inhibit the PD1/PDL1 interaction
B) They bring T cells and cancer cells in close proximity to facilitate T cell mediated cytotoxicity
C) They stimulate the innate immune system to recognize tumor cells.
D) They increase neoantigens.
B) They bring T cells and cancer cells in close proximity to facilitate T cell mediated cytotoxicity
what cancer type has had the best success in CAR T cell therapy specific for CD19?
B cell leukemias
