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therapeutics 864 - exam 1 > immunotherapies > Flashcards

immunotherapies Flashcards

1
Q

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

A

Melanoma

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2
Q

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

A

increasing in cell size

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3
Q

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.

A

-It uses some kind of genetic testing to indicate therapy or predict for tumor recurrence.

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4
Q

REVIEW

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

Hyperplasia
Dysplasia
Metaplasia
Desmoplasia

A

metaplasia

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5
Q

REVIEW

Which is of the following is an example of a tumor suppressor?

BRCA
HER2
CDK4/6
HPV

A

BRCA; loss of BRCA results in breast cancers

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6
Q

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

A

Coley’s toxin; mixed bacterial vaccine

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7
Q

t/f Coley’s toxin is FDA approved

A

false

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8
Q

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

A

true

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9
Q

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

A

b cells

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10
Q

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

A

antibodies

variable domain & constant domain

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11
Q

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

A

mice; hydridomas

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12
Q

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

A

patient’s immune system.

molecular biology and protein expression

complementarity determining region

VDJ

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13
Q

nomenclature & monoclonal antibodies:

what is them of all monoclonal antibodies?

substems:
-mouse =
-chimeric =
-humanized =
-fully human =

A

-mab

-mouse = o
-chimeric = xi
-humanized = zu
-fully human = u

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14
Q

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 ___________.

A

inhibit

complement-dependent cytotoxcity

antibody-dependent cellular cytotoxicity

kinase inhibitors

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15
Q

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

A

ErbB

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16
Q

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

A

TRUE

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17
Q

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

A

humanized

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18
Q

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

A

HER2

antibody-dependent cellular cytoxicity (ADCC)

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19
Q

HER2 protein is overexpressed in ________% of all breast cancers

A

25-30%

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20
Q

a pt has breast cancer that is HER2 negative, is trastuzamb (herceptin) a good tx option?

A

No, herceptin is specific for HER2 and therefore indicated for tx of breast cancers that overexpress HER2

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21
Q

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

A

> all of the above

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

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22
Q

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

A

HER2

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23
Q

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

A

dimerization; dimerize

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24
Q

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

A

dimerization of HER2

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25
Q

what trial was used to show efficacy of pertuzumab & trastuzumab combo therapy?

A

CLEOPATRA

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26
Q

what is the 1st line combo therapy for HER2+ breast cancers

A

taxane, pertuzumab & trastuzumab

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27
Q

what is an administration limitation of the combo med, Phesgo (pertuzumab & trastuzumab)?

A

IV only, cannot be used at home

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28
Q

_____ engineering can improve immune activation by therapeutic antibodies. Margetuximab is an example of this (SOPHIA trial).

A

Fc

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29
Q

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

A

chimeric; EGF

EGF & TGF-alpha

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30
Q

The primary indication for cetuximab is _________ and _______ cancers

A

colorectal & head/neck cancers

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31
Q

why is there a warning with cetuximab?

what are 3 other expected toxicities? why are they expected?

A

~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

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32
Q

panitumamab is a _______ monoclonal antibody that binds specifically to the extracellular domain of ______ receptor

A

fully humanized; EGF

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33
Q

what toxicity only occurs with cetuximab & not panitumumab?

A

infusion toxicity

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34
Q

what are the 2 drugs that competitively inhibit binding of EGF & TGF-alpha?

A

cetuximab & panitumumab

> similar SE profile

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35
Q

what cancer is indicated for cetuximab & not panitumumab?

A

head & neck is only cetuximab

both are colorectal

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36
Q

Bevacizumab & Ramucirumab bind to __________. However, _______ binds the ligand & __________ binds the receptor

A

VEGF; bevacizuman; ramucirumab

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37
Q

t/f there is efficacy of bevacizumab as a single agent for metastaic colorectal cancer

A

false; must be used as combo

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38
Q

what are VEGF blockers (i.e bevacizumab) used in combo with for 1st line tx of metastatic _______ cancer

A

5-FU; colorectal

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39
Q

Which of the following antibodies targets Her2?

Neratinib
Cetuximab
Lapatinib
Pertuzumab

A

Pertuzumab

> cetuximab is EGF receptor target, Neratinib & lapatinib are kinase inhibitors

40
Q

Explain the two tiered targeting affect of antibody therapy as compared to small molecule kinase inhibitors?

A

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

41
Q

What was the first immunotherapy?

Pertuzumab
Keytruda
Coley’s toxin
Trastuzumab

A

Coley’s toxin

42
Q

The antibody Fakeumab has just entered the market. What type of the antibody was it?

Fully human
Humanized
Fully mouse
Chimeric

A

Fully human

43
Q

Describe why the combined use pertuzumab and trastuzumab both defies and complies with general rules of combination therapy?

A

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

44
Q

what is a primary target in B-cell lymphoma?

CD20
CD19
CD22
CD38

A

CD20

45
Q

CD20 works with which receptor to drive proliferation of B cells

A

B-Cell receptor (BCR)

CD20 also plays role in proliferation of B cell lymphomas

46
Q

_______ binding to CD20 inhibits B cell proliferation and __inhibits/induces___ Antibody-dependent cytotoxicity (ADC)

A

Antibody binding to CD20 inhibits B cell proliferation and induces Antibody-dependent cytotoxicity

47
Q

rituximab is a ________ monoclonal antibody

A

chimeric

48
Q

what chimeric monoclonal antibody binds to CD20?

A

rituximab

49
Q

CD20 is expressed by normal B lymphocytes and __mature/immature__pre-B cells

Also expressed on > __#__% of B-cell non-Hodgkin’s lymphoma cells

A

immature; 90%

50
Q

why are rituximab & ofatumumab similar?

A

both are specific for CD20

51
Q

ofatumumab is a _________ monoclonal anitbody developed to tx CLL & b-cell lymphomas

A

fully humanized

52
Q

t/f CD20 is expressed normally on B cells, not just B cells in lymphoma

A

true

53
Q

CD38 is a multifunctional transmembrane protein highly expressed on _____ B cells that make antibodies

Multiple Myeloma is a cancer of malignant ________ cells

A

plasma

Myeloma; plasma

54
Q

Daratumumab is a ______ monoclonal antibody that targets _______ that eliminate multiple myeloma cells by ADCC or CDC.

This also eliminates ______ _______cells

A

fully humanized; CD38

Natural killer (innate immunity)

55
Q

what monoclonal antibody also eliminates natural killer cells involved in innate immunity?

A

daratumumab

56
Q

Trastuzumab Emtansine (TDM1) is a ________-______ conjugate.

Emtansine enters cells & inhibits ________ assembly

what is TDM1 approved to tx?

A

antibody-drug

microtubule (emtansine is cytotoxic agent)

2nd line tx of HER2+ metastatic breast cancer

57
Q

emtansine is a modified version of ______, a tubulin inhibitor

A

mertansine

58
Q

trastuzumab-deruxtecan is unique because deruxtecan is a ________ inhibitor

A

TOPO 1 inhibitor

59
Q

What are the 2 major issues for T cell based immunotherapy?

A

> central tolerance
immunosuppression/peripheral tolerance
(immune system has already become tolerant to the cancer which is why it’s growing)

60
Q

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

A

Central

Peripheral

61
Q

The T in T cell refers to what?

A

thymus

62
Q

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__

A

apoptosis

negative = too tight

non selection = too loose

63
Q

T cell activation require _______ to be presented to them by membrane bound _____

A

antigens; MHC

64
Q

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)
A

MHC

activated

antigen

memory

65
Q

what are the 3 strategies to overcoming central tolerance?

A
  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
66
Q

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

A

T & B cell

67
Q

t/f BiTEs are chimeric antibodies

A

FALSE

68
Q

Blinatumomab is an example of a _____ that target T cells to receptors highly expressed on cancers

A

BiTEs

69
Q

BiTE antibodies bind _____ to physically bring an activated ___ cell into proximity with _____, which is highly expressed on B cells & acute lymphoblastic leukemia

A

CD3; T cell; CD19

70
Q

what transmembrane protein (CDs) does mosunetuzumab target on non-Hodgkin lymphomas?

A

CD3 & CD20

71
Q

cytokine release syndrome is a SE for what drug(s)?

A

mosunetuzumab (immunotherapies & BiTEs)

> basically When t cells are activated, the immune system is activated which releases cytokines and can lead to cytokine storm

72
Q

Teclistamab is a BiTE that targets _____ on T cells & b cell maturation antigen (BCMA) on multiple myeloma cells

A

CD3

73
Q

what are the 4 BiTEs that we covered?

which two are indicated for multiple myeloma?

A

blinatumomab
mosunetuzumab
teclistamab -MM
taquetamab -MM

74
Q

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

A

TRUE

75
Q

______ and _______ act as brakes or checkpoints on the immune system

so blocking these interactions w antibodies can reactivate ___ cells

A

CTLA-4 and PD1

T cells

76
Q

ipilimumab is a recombinant ___ monoclonal antibody that binds to the _____ receptor & reverses the ____ inhibition

A

CTLA-4; CTLs (cytotoxic T lymphocytes-able to recognize & destroy malignant tumor cells)

77
Q

why might ipilimumab require high dose corticosteroids?

A

severe immune related inflammatory response adverse rxn
>GI tract, dermatitis, neuropathy & endocrinopathy

78
Q

pembrolizumab (keytruda) binds to _______ receptor and blocks its interactio with ___ ligand 1 & 2

A

PD-1 & PD

79
Q

t/f PD-1 is expressed on t cells, while PD-L1 is expressed on macrophages & tumor cells

A

true

blockade of PD1 prevents inhibitory signaling within t cell leading to enhanced tumor cell killing

80
Q

Ipilimumab and pembrolizumab treat what kind of cancer

A

advanced metastatic melanoma

pembrolizumab also for NSCLC if PD-L1+ in biopsy

81
Q

what must a pt be treated with prior to receiving pembrolizumab (keytruda)

A

ipilimumab & BRAF inhibitor (if BRAF V600 +)

82
Q

atezolizumab binds to _____ and blocks interaction with ________

A

PD-L1 (macrophages/tumor cells); PD-1 (t cells)

83
Q

sipulcel-T is a therapeutic _______ that contains ___-___-___, an immune cell activator

A

vaccine; PAP-GM-CSF

84
Q

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?

A

APCs; leukapheresis

85
Q

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

A

false; EX VIVO

86
Q

t/f The goal of sipulcel-T reinfusion is the stimulate a pt’s own immune system to attack the cancer

A

true

87
Q

Sipulcel-T (provenge) is idnicated for what cancer?

A

metastatic hormone-refractory prostate cancer

88
Q

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

A

TRUE

89
Q

generally T cell activation is complex and requires activation of multiple proteins, so co-stimulatory receptors are added to a single ______

A

CAR (chimeric antigen receptor)

> it’s how it gets the “chimeric” part of name

90
Q

after tx with CAR T cell therapy can pt develop same cancer later in life?

A

No, lifetime immunity to that cancer, but they can develop other cancers

91
Q

CD__#__ CAR-T treatments are common and eliminate all immature b cells

A

19

92
Q

Which antibody is effective against metastatic melanoma and targets CTLA-4?

Ipilimumab

Trastuzumab

Daratumumab

Blinatumomab

A

Ipilimumab

93
Q

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

A

PDL1

94
Q

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

A

B) CD19

95
Q

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.

A

B) They bring T cells and cancer cells in close proximity to facilitate T cell mediated cytotoxicity

96
Q

what cancer type has had the best success in CAR T cell therapy specific for CD19?

A

B cell leukemias

therapeutics 864 - exam 1 (10 decks)

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