immunotherapies Flashcards by Hannah Eberle

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

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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

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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.

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REVIEW

Which of the following terms is associated with substitution of tissue type for another?

Hyperplasia
Dysplasia
Metaplasia
Desmoplasia

metaplasia

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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

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_________ is sometimes referred to as MBV for _____ _________ _______, and was the first attempt to use immunotherapy & hyperthermia against cancer

Coley’s toxin; mixed bacterial vaccine

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t/f Coley’s toxin is FDA approved

false

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t/f adaptive immunity involves T cells, B cells & plasma cells

true

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which cells of the adaptive immune system produce antibodies (aka antigen presenting cells)

b cells

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__________ are the humoral arm of the immune system. what are the two domains that make these up?

antibodies

variable domain & constant domain

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we often make antibodies in animals such as, _____. this produces ________ that are then screened for production and cloned into monoclonal antibodies

mice; hydridomas

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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

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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

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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

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A focus for Mab’s is the ______ family of growth factor receptors

ErbB

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t/f HER2 is an oncogene & receptor tyrosine kinase that is genomically amplified in breast cancer

TRUE

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based on the substem what is trastuzumab
-mouse
-chimeric
-humanized
-fully human

humanized

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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)

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HER2 protein is overexpressed in ________% of all breast cancers

25-30%

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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

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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

SE profile is similar to kinase inhibitors; but hypersensitivity is unique to immunotherapy

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Pertuzumab (perjeta) is a recombinant humanized monoclonal antibody specific for _________

HER2

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HER2 _______is an important element of optimal HER2 response. When HER2 is increased like in many breast cancers it tends to ________

dimerization; dimerize

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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

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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).

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: 1. a naïve T-cell encounters antigen in combination with ____ 2. 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 3. 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?

1. Redirect T cells to cancer using genetic means (Bispecific T cell engager - BiTE) 2. Redirect T cells to cancer using recombinant proteins 3. 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

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