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Therapeutics IV > Oncology Immunotherapy_Edit > Flashcards

Oncology Immunotherapy_Edit Flashcards

1
Q

What is Coley’s toxin (aka MBV)?

A

First attempt to use immunotherapy and hyperthermia against cancer

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2
Q

Define positive selection

A

permits the survival of only those T-cells whose TCRs are capable of recognizing self-MHC molecules

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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3
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

extremely important factor in GENERATING A PRIMARY T-CELL REPERTOIRE THAT IS SELF-TOLERANT

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4
Q

Antibody production is the

A

humoral arm of the immune system

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5
Q

substem of all monoclonal antibodies

A

-mab

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6
Q

substem of mouse antibody

A

-o

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7
Q

substem of chimeric antibody

A

-xi

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8
Q

substem of humanized antibody

A

-zu

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9
Q

substem of fully human antibody

A

-u

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10
Q

What is genomically amplified in breast cancer

A

Her2 (overexpressed in 25 - 30% of all breast cancers)

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11
Q

Trastuzumab specific for

A

Her2

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12
Q

Trastuzumab indication

A

tx of breast cancer that overexpress Her2

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13
Q

Pertuzumab specific for

A

Her2

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14
Q

Pertuzumab capable of

A

binding to Her2 and INHIBITING DIMERIZATION

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15
Q

Pertuzumab used in combination with

A

Trastuzumab

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16
Q

Pertuzumab indicated

A

in combination with trastuzumab and docetaxel for tx of patients with Her2-positive metastatic breast cancer (MBC) who have not received prior anti-Her2 therapy or chemotherapy for metastatic disease

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17
Q

Can pertuzumab be used at home

A

NO

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18
Q

Which domains do trastuzumab and pertuzumab bind to?

A

T = 4

P = 2

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19
Q

Margetuximab

A

showed slightly better survival in pretreated patients as compared to trastuzumab (SOPHIA trial). Approved in December 2020

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20
Q

Cetuximab binds to

A

EGF receptor

competitively inhibits binding of EGF and TGF-alpha

blocks phosphorylation and activation of receptor-associated KINASES

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21
Q

Cetuximab primary indication

A

tx of colorectal and head and neck cancers

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22
Q

What SE associated with EGFR-inhibition

A

anciform rash

associated with positive disease response

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23
Q

Panitumumab binds

A

binds to domain of EGF receptor

competitively inhibits binding of EGF and TGF-alpha

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24
Q

Panitumumab indication

A

tx of colorectal cancer

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25
Q

Explain 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.

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26
Q

Describe why the combined use of 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

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27
Q

Administration of cetuximab and panitumumab for the tx of metastatic colorectal cancer now requires

A

KRAS mutational status

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28
Q

CD20 works with

A

the B-cell receptor (BCR) to drive proliferation of B-cells

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29
Q

CD20 also plays a role in

A

the proliferation of B-cell lymphomas

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30
Q

Ofatumumab is specific for

A

CD20

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31
Q

CD20 is expressed by normal

A

B lymphocytes and immature pre-B cells

32
Q

Ofatumumab indication

A

is in the tx of B-cell non-Hodgkin’s lymphoma

33
Q

Bevacizumumab specific for

A

vascular endothelial growth factor (VEGF)

34
Q

Bevacizumumab fact

A

no evidence of efficacy as a single agent

35
Q

Bevacizumumab used in combination with (indication)

A

5-FU based chemotherapy for FIRST-LINE tx of metastatic colorectal cancer

36
Q

Bevacizumumab binds the ______ while ramucirumab binds the _________

A

ligand; receptor

37
Q

What is Trastuzumab Emtansine?

A

Antibody-drug conjugate consisting of the cytoxic agent linked to the monoclonal antibody trastuzumab

38
Q

Trastuzumab binds to

A

Her2/Neu receptor and leads to usual herceptin response

39
Q

Emtansine does what

A

enters cells and inhibits microtubule assembly

emtansine toxicity significantly reduced because of Her2 targeting

40
Q

Trastuzumab Emtansine indication

A

2nd line tx for Her2-positive metastatic breast cancer

41
Q

Trastuzumab conjugated with what other drugs

A

deruxtecan

the “tecans” are TOPOI inhibitors

42
Q

Describe Lymphomas

A

arise from cells that populate lymph notes

i.e. hodgkin’s lymphoma

(locate reed-sternberg cells)

43
Q

Brentuximab vedotin is a

A

anti-CD30 antibody conjugated to monomethyl auristatin E (MMAE)

44
Q

Reed-sternberg cells associated with

A

lymphomas

45
Q

Reed-sternberg cells express

A

CD30

46
Q

What is MMAE

A

a microtubule destabilizing agent, ~200 times more potent than vinblastine

toxic by itself. must be conjugated to an antibody

47
Q

Major issues for T cell-based immunotherapy

A
  • central tolerance: repertoire to self is irrevocably compromised
  • immunosuppression/peripheral tolerance
48
Q

Interleukin-2 is a

A

recombinant protein

multiple immunologic effects

highly pro-inflammatory cytokine

extremely nonspecific

49
Q

CTLA-4 and PD1 act as

A

brakes or checkpoints in the immune system

50
Q

Blocking CTLA-4 and PD1 with antibodies

A

keeps T-cells activated

51
Q

Ipilimumab binds to

A

CTLA-4 receptor and reverses the CTL inhibition

52
Q

Ipilimumab indication

A

tx of advanced metastatic melanoma

may require high-dose corticosteroids

53
Q

Pembrolizumab, Nivolumab, Cemiplimab all bind

A

the program death-1 (PD-1) receptor and blocks its interaction with PD-Ligand 1 and 2 (PD-L1 and PD-L2)

54
Q

Where is PD-1 expressed?

A

T-cells

55
Q

Blocking PD-1

A

prevents inhibitory signaling within T-cells leading to enhanced tumor cell killing

56
Q

Pembrolizumab, Nivolumab, Cemiplimab indication

A

advanced metastatic melanoma following tx w/ 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

57
Q

Atezolizumab, Avelumab, Durvalumab bind

A

PD-L1 receptor and block interaction with PD-1

58
Q

Where is PD-L1 expressed

A

macrophages and tumor cells

59
Q

Atezolizumab, Avelumab, Durvalumab indication

A

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

60
Q

Sorafenib is a

A

multi-target kinase inhibitor

hits RAF, VEGFR, PDGFR

61
Q

Sorafenib indication

A

unresectable liver cancer

62
Q

anti-tumor immunity can be enhanced by

A

preceding it w/ radiation

63
Q

radiation produces

A

neo-antigens

64
Q

How do Bi-specific T-cell Engagers (BiTE) work?

A
  • act independently of specificity of T-cell receptor (TCR)
  • allow T-cells recognition of tumor-associated surface antigen (TAA)
  • Do not require MHC Class I and/or peptide antigen
65
Q

Blinatumomab binds to

A

CD19 and CD3

physically brings an activated T-cell into proximity with the tumor cell

activated T-cell will then lyse the tumor cell

66
Q

Blinatumomab indication

A

B-cell lymphomas

DON’T CONFUSE THESE WITH CHIMERIC ANTIBODIES

67
Q

What does CARs stand for?

A

Chimeric Antigen Receptor

68
Q

What is CAR T-cell Therapy

A
  • remove blood from pt to get T-cells
  • Make CAR T cells in the lab
  • Grow millions of CAR T cells
  • Infuse CAR T cells into pt
  • CAR T cells bind to cancer cells and kill them
69
Q 
Tisagenlecleucel (Kymriah)
Brexucabtagene autoleucel (Tecartus)
Axicabtagene Ciloleucel (Yescarta)
Lisocabtagene maraleucel (Breyanzi)

are examples of

A

CAR T-cell therapy

pt is essentially immunized against CD-19

All immature B-cells are eliminated

The T-cells live on indefinitely

70
Q

The future of T-cell therapy

A

the best success has been in B-cell leukemia’s in which the CAR is specific for CD19

adopting this same approach into other tumor types has been a challenge due to toxicity

Need a way to turn the CAR T-cells off

71
Q

Sipuleucel-T approved for

A

metastatic prostate cancer

72
Q

Sipulcel-T is a

A

“Drug” is PAP-GM-CSF, a recombinant human protein containing prostatic acid phosphatase (PAP) linked to granulocyte macrophage colony stimulating factor (GM-CSF), an immune cell activator

goal = stimulate a pt’s own immune system to attack the cancer

73
Q

Sipulcel-T indicated for

A

tx of minimally symptomatic metastatic hormone-refractory prostate cancer

74
Q

Hepatitis B Virus (HBV) associated w/

A

liver cancer

75
Q

HPV Vaccines

A

Human Papilloma Virus (HPV) can act as a primer for cancer development
-HPV is a DNA virus that produces proteins (E6 and E7) that increase cell proliferation and allow for accumulation of DNA mutations.
-HPV types 16 and 18 are the major causative agents for cervical cancer and therefore can be vaccinated against as means to prevent HPV infection and hence cervical cancer.
- Also predicted to protect against vuvlar, vaginal, anal and penile cancers that are associated with HPV infection.
Quadrivalent HPV (HPV4, Gardasil)
Is made up of the major capsid protein L1 of HPV types 6, 11, 16, and 18
Bivalent HPV (HPV2, Cervarix)
Is made up of the major capsid protein L1 of HPV types 16, and 18

Both administered in three doses over a period of 6 months.

Therapeutics IV (19 decks)

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