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Therapeutics IV > Oncology Immunotherapy - Dr. Wendt > Flashcards

Oncology Immunotherapy - Dr. Wendt Flashcards

1
Q

Name a drug that targets HER2

A

Tucatinib

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2
Q

Name a drug that targets a kinase that is produced by formation of the Philadelphia chromosome

A

Imatinib (exam question)

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3
Q

Name a compound that is not a covalent kinase inhibitor

A

Gefitinib

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4
Q

What TYPE of kinase inhibitor can bind in the ATP sight and stabilize the inactive conformation of a kinase

A

Type II

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5
Q

Name a drug that prevents the phosphorylation of lipids

A

Alpelesib

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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

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7
Q

What might the next course of BCR-Abl-targeted therapy might include?

A

Ponatinib is indicated upon identification of the T315I mutation

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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

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9
Q

In 1953 ______ pharmaceutical companies were producing different versions of ____________

A

two; Coley’s toxin

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10
Q

___________ has changed the face of cancer therapy

A

T-cell targeting

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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

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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

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13
Q

T-cells arise in the bone marrow BUT migrate to the ________ for maturation

A

thymus

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14
Q

T-cells don’t recognize antigen alone, but recognize antigen (small peptides) presented to them by _______________

A

cell-membrane bound MHC

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15
Q

Name types of T-cells

A
  • helper T-cells – CD4
  • cytolytic T-cells – CD8
  • Regulatory T-cells
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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)

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17
Q

Antibody production: the __________ of the immune system

A

humoral arm

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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.
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19
Q

Stem of all monoclonal antibodies is _____

A

-mab

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20
Q

substem that indicates mouse

A

-o

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21
Q

substem that indicates chimeric

A

-xi

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22
Q

substem that indicates humanized

A

-zu

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23
Q

substem that indicates fully human

A

-u

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24
Q

Antibody binding can lead to several _________ events

A

anticancer

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25
Q

binding of large protein complexes such as antibodies to cell surface receptor often times will _________ their function

A

inhibit

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26
Q

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

A

complement-dependent cytotoxicity; anti-body-dependent cellular cytotoxicity (ADCC); selective elimination

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27
Q

This ____________ affect may be why blocking antibodies have unique effects over _____________

A

two tiered; kinase inhibitors

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28
Q

HER2 is also…

A

…p185

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29
Q

______ is genetically amplified in ____________

A

HER2; breast cancer

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30
Q

Trastuzumab brand

A

Herceptin

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31
Q

What is trastuzumab?

A

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

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32
Q

HER2 is overexpressed in ____________ of all breast cancers

A

25-30%

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33
Q

Herceptin binds to receptor and induces __________-__________ ____________ ___________. It also induces receptor ______________ and _______________

A

antibody-dependent cellular toxicity; internalization; degradation

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34
Q

Primary indication of Herceptin…

A

…is in the treatment of breast cancers that overexpress HER2

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35
Q

Toxicities of Herceptin

A

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)

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36
Q

Pertuzumab brand

A

Perjeta

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37
Q

What is Pertuzumab

A

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

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38
Q

What drug involved the CLEOPATRA trial

A

pertuzumab

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39
Q

What happened during the CLEOPATRA trial?

A

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.

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40
Q

Can the pertuzumab/trastuzumab combo product be used at home?

A

No

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41
Q

Trastuzumab binds at the _____ location

A

IV

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42
Q

Pertuzumab binds at the _____ location

A

II

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43
Q

__ engineering can improve immune activation by therapeutic antibodies

A

Fc

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44
Q

________________ showed slightly better survival in pretreated patients as compared to ________________

A

Margetuximab; trastuzumab (SOPHIA trial)

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45
Q

Cetuximab brand

A

Erbitux

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46
Q

What is Cetuximab?

A

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

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47
Q

EGF receptor is constitutively expressed in many normal epithelial tissues. Receptor is overexpressed in many ______ ___________

A

human cancers

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48
Q

Primary indication of Cetuximab…

A

…is in the treatment of colorectal and head and neck cancers

49
Q

Toxicities of Cetuximab

A

WARNING! Severe infusion reaction in ~ 3% of patients – usually 1st dose:

  • Acneiform rash
  • Asthenias
  • Fever
50
Q

The ________ ____ is associated with ____________. Occurence of the rash is __________ associated with disease response.

A

anciform; EGFR-inhibition; positively

51
Q

Panitumumab brand

A

Vectibix

52
Q

What is panitumumab?

A

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
Q

How often is panitumumab given?

A

every 2 weeks

54
Q

SE of panitumumab

A

Skin rash and other cutaneous side effects (this predictive of better clinical outcome)

Diarrhea

55
Q

Primary indication of panitumumab…

A

…is in the treatment of colorectal cancer

56
Q

Panitumumab does not carry any ______________

A

infusion toxicities

57
Q

Name an antibody that targets HER2

A

Pertuzumab

58
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 along with activation of the ADCC can lead to differential therapeutic outcomes when using antibodies as compared to the small molecules.

59
Q

What was the first immunotherapy?

A

Coley’s toxin

60
Q

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

A

Against: Shared target equals shared toxicities.

For: Different bindings sites on HER2, different mechanisms of HER2 inhibition, enhanced activation of the ADCC.

61
Q

Signaling pathways are __________ events. In fact, administration of cetuximab and panitumumab for the treatment of __________ _________ _______now requires ______ ______________ status

A

sequential; metastatic colorectal cancer; KRAS mutational

62
Q

CD20 works with the _-____ ________ to drive the proliferation of __-_____

A

B-cell receptor (BCR); B-cells

63
Q

CD20 also plays a role in the proliferation of _-____ _____________

A

B-cell lymphoma

64
Q

Ofatumumab is a…

A

…fully human monoclonal antibody specific for CD20

65
Q

Ofatumumab is a ____________ protein that regulates an early step in activation of cell cycle ____________ and _______________

A

transmembrane; initiation; differentiation

66
Q

CD20 is expressed by normal __ __________________ and ____________ ___-__ _____. It is also expressed on > 90% of B-cell ___-__________ ______________ _____

A

B lymphocytes; immature pre-B cells; non-Hodgkin’s lymphoma cells

67
Q

Primary indication of Ofatumumab…

A

…is in treatment of B-cell non-Hodgkin’s lymphoma

68
Q

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

A

CD20; binding sites; Lymphoid; Myeloid

69
Q

Bevacizumab brand

A

Avastin

70
Q

What is Bevacizumab?

A

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
Q

For Bevacizumab, there is…

A

…no evidence of efficacy as a single agent

72
Q

Bevacizumab indication

A

used in combination with 5-FU based chemotherapy for first-line treatment of metastatic colorectal cancer

73
Q

Bevacizumab binds the ______, Ramucirumab binds the ________. There are an array of small molecules that inhibit the kinase activity.

A

ligand; receptor

74
Q

What does ADC stand for?

A

Antibody Drug Conjugates

75
Q

Trastuzumab Emtansine brand

A

Kadcyla

76
Q

What is Trastuzumab?

A

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
Q

Trastuzumab indication

A

approved as second line treatment for HER2-positive metastatic breast cancer

78
Q

Additional drugs being conjugated to trastuzumab…

A

…is trastuzumab-deruxtecan. The “tecans” are TOPOI inhibitors

79
Q

Trastuzumab toxicites

A

Adverse effects of trastuzumab (as expected)

Thrombocytopenia (mertansine effect)

Hepatotoxicity (mertansine effect)

80
Q

Lymphomas arise from cells that populate ________ ______

A

lymph nodes

81
Q

Brentuximab vedotin brand

A

Adcetris

82
Q

What is brentuximab vedotin?

A

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
Q

The major goal and challenge of cancer immunotherapy is to…

A

..direct the immune system to recognize and destroy cancer

84
Q

At the point where the tumor is established, natural balance has fundamentally ___________ against the ability to mount an effective ________ _________

A

shifted; immune response

85
Q

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

A
  • central tolerance: repertoire to self is irrevocably compromised
  • immunosuppression/peripheral tolerance
86
Q

What percentage of T-cells are deleted?

A

98%

87
Q

What does central tolerance entail?

A

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
Q

_________ ______________ points are likely to be required for maximally effective implementation of immunotherapy

A

Multiple Intervention

89
Q

Established tumors have developed a breadth of mechanisms to counterbalance anti-tumor immunity: ____________ ___________ needed to address multiple steps in the immune process

A

Combination therapies

90
Q

Interleukin-2 brands

A

Proleukin + Aldesleukin

91
Q

What is interleukin?

A

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
Q

Interleukin indications

A

variety

93
Q

T or F: Interleukin is extremely nonspecific

A

TRUE

94
Q

Interleukin toxicities

A

fever

malaise

fatigue

anorexia

95
Q

__________ intervention points are likely to be required for __________ effective implementation of immunotherapy

A

multiple; maximally

96
Q

Established tumors have developed a breadth of mechanisms to _______________ anti-tumor immunity: ______________ therapies needed to address multiple steps in the immune process

A

counterbalance; combination

97
Q

CLTA-4 and PD1 act as _________ or _____________ on the immune system. Blocking these interactions with antibodies keeps T-cells ____________

A

brakes; checkpoint; activated

98
Q

Ipilimumab brand

A

Yervoy

99
Q

What is ipilimumab

A

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
Q

T or F: Ipilimumab has a unique mechanism of action

A

TRUE

101
Q

Ipilimumab indications

A

approved for treatment of advanced metastatic melanoma

102
Q

Ipilimumab adverse reactions

A

severe immune-mediated adverse reactions

generally related to inflammatory response:

  • GI tract (enterocolitis, hepatitis)
  • Dermatitis, neuropathy, endocrinopathy

may require high-dose corticosteroids

103
Q

Pembrolizumab brand

A

Keytruda

104
Q

Nivolumab brand

A

Opdivo

105
Q

Cemiplimab brand

A

Litayo

106
Q

What are pembrolizumab, nivolumab and cemiplimab?

A

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
Q

pembrolizumab, nivolumab and cemiplimab indications

A

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
Q

Atezolizumab brand

A

Tecentriq

109
Q

Avelumab brand

A

Bavencio

110
Q

Durvalumab brand

A

Imfinzi

111
Q

What are tezolizumab, avelumab, and durvalumab?

A

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
Q

tezolizumab, avelumab, and durvalumab indications

A

NSCLC in patients with EGFR or ALK mutations that have progressed on those therapies

indications will continue to grow

113
Q

tezolizumab, avelumab, and durvalumab exclusions

A

autoimmune disease

medical conditions requiring immunosuppression

114
Q

What is sorafenib?

A

multi-target kinase inhibitor, hitting RAF, VEGFR, PDGFR and others. Approved in unresectable liver cancer

115
Q

Antitumor immunity can be enhanced by preceding it with ___________

A

radiation

116
Q

radiation produces ____________

A

neo-antigens

117
Q

What is BiTE?

A

Bi-specific T-cell Engager

118
Q

What is Blinatumomab?

A

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.

Therapeutics IV (19 decks)

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