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Hot Topics > Epigenetics and Immunotherapy > Flashcards

Epigenetics and Immunotherapy Flashcards

1
Q

What is epigenetics?

A

Epigenetics refers to the changes in gene expression that are not caused by changes in DNA sequence

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2
Q

What is methylation?

What is it?
Where does it occur?
What does it lead to?

A

The addition of a methyl group to the cytosine residue of the DNA. It can occurs on histone tails or directly to the DNA

DNA methylation leads to gene Inactivation (contracts/coils)

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3
Q

What is acetylation

A

Addition of acetyl group to the lysine residue of histone protein.

Leads to gene activation: separation of histones/DNA

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4
Q

What enzymes are responsible for methylation?
Explain their role(s)

A

DNMT1 - for the maintenance of methylation

DNMT3A
DNMT3B - both responsible for the methylation start process (De novo methylation process)

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5
Q

State the main therapeutic cancer epigenome targets (groups)

A

Broad spectrum reprogrammers
Narrow spectrum reprogrammers

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6
Q

Give examples of broad spectrum reprogrammers

A

DNMT1 inhibitors
HDAC inhibitors

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7
Q

What is DNMT1

A

The enzyme responsible for the maintenance of the methylation process

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8
Q

What cancer does DNMT1 inhibitors treat?

A

acute myelogenous leukaemia

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9
Q

DNMT1 inhibitor use, example, MOA and Side effects

A

5-Azacytidine
Use: acute myelogenous leukaemia
MOA: inhibits the enzyme responsible for the maintenance of methylation process, therefore less methylation = more tumour suppressor gene
Side effects: Infection, haemorrhage, Nausea and vomiting

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10
Q

What is HDAC

A

Histone deaceytlase, it induces chromatin closing

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11
Q

What are HATs

A

Histone acyetlation, induces chromatin opening

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12
Q

HDAC inhibitor example, MOA and side effects

A

Chidamide
MOA:
inhibits histone deacetylase enzyme which is responsible for inducing chromatin closing/condensation. =leads to the activation of TSG

Side effects: Nausea, Fatigue, Fever

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13
Q

what disease are HDAC inhibitors used in?

A

Breast cancer

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14
Q

Give examples of narrow spectrum reprogrammers

A

EZH2 inhibitors

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15
Q

What is EZH2

A

EZH2 is a catalytic component of PRC2
It catalyses the tri-methylation of histone H3 at lysine 27 (H3K27me3) to promote transcriptional silencing

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16
Q

What does EZH2 promote?

A

Cell survival, proliferation, invasion and drug resistance of cancer cells

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17
Q

Give an example of an EZH2 inhibitor

A

Tazemetostat

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18
Q

What does Tazemetostat treat?

A

Follicular lymphoma (subtype of B-cell cancer)
EZH2 has overexpression or mutation in FL

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19
Q

EZH2 inhibitor example, MOA and side effects

A

Tazemetostat
Inhibits EZH2 protein > inhibiting lymphoma cell growth
(by inhibiting trimethylation of H3K27me3) to promote trancription silencing
= activation of TSG
Side effects: Nausea, low energy, constipation

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20
Q

Define Immunotherapy?

A

Immunotherapy harnesses the body’s own immune system to prevent , control and eliminate cancer.

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21
Q

List the different Immune cells

A

Dendritic cells (DCs)
Macrophages
Natural Killer cells
B CELLS
Cytotoxic T cells
Helper T cells

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22
Q

List the cells part of the innate immune system

A

Dendritic cells (DCs)
Macrophages
Natural Killer cells

23
Q

List the cells part of the adaptive immune system

A

B cells
Cytotoxic T cells
Helper T cells

24
Q

Describe T cell activation

A

T cell receptor (TCR) binds to antigen loaded MHC complex on antigen-presenting cells (APCs)

CD8/4 molecules bind on MHC

(Co-stimulatory molecules are needed)

CD28 co Stimulatory molecule on T cells bind to B7.1/2 on APCs

=

T cell proliferation

25
Q

Name a cancer vaccine, what it’s used for, the MOA and its side effects

A

Provenge (Sipuleucel-T)
Use: For advanced prostate cancer
MOA: Antigen presenting cells (APCs) are activated with granulocyte-macrophage colony stimulating factor (GM-CSF) and presenting prostatic acid phosphate (PAP) cancer specific antigen
Side effects: Nausea, fever, joint aches

26
Q

Name an oncolytic virus therapy, what it’s used for, the MOA and its side effects

A

T-VEC (Imlygic)
Use: Melanoma
MOA: A modified herpes simplex virus (HSV) (uses virus to infect and destroy cancer cells)
Insertion of an immune-stimulating gene and removal of disease causing gene = selective targeting of tumour
Side effects: Injection site pain, nausea, fever and fatigue

27
Q

Describe ‘man made’ cytokines, give examples and list 3 side effects

A

They boost the activity of the immune system

Interleukins (e.g. IL-2) for Kidney cancer & melanomas
IL-2 increases the no of T and NK cells
(However causes Vascular leakage syndrome)

Interferons (IFN-ga) for leukemia, melanoma and lymphoma

Side effects; nausea, fatigue and bleeding (vascular leakage syndrome)

28
Q

What is Provenge (Sipuleucel-T)?

A

A cancer vaccine used in the treatment of advanced prostate cancer

29
Q

What is T-VEC (Imlygic)?

A

An oncolytic virus therapy used in the treatment of melanomas
(modified herpes simplex virus)

30
Q

Describe Adoptive cell transfer/T-cell therapy.

A

Collect blood samples (for immune cells)
Grow samples
Re-inject back into patients (T-cells recognise and kill cancer cells).

*Patients must be immunocompromised with chemo or radiation to reduce patients own immune cells

31
Q

What is CAR-T cell therapy?

A

Chimeric antigen receptor T cells

T cells are engineered to produce CAR T cell receptors

CARS (either autologous or allogenic) enables T cells to target specific antigens on cancer cells

32
Q

What is chimeric?

A

Combines antigen binding and T cell activating functions in one receptor

33
Q

What can CAR-T therapy treat?
Describe the applications of CAR-T therapy.

A

Haematological malignancies

CD19 (….) is expressed in lymphomas (found in B cells) = most popular antigen target

BCMA (…) expressed in multiple myeloma = second popular target

34
Q

What antigens/cells are popular CAR-T targets?

A

CD19…

BCMA…

35
Q

Why isn’t CAR-T therapy effective for solid tumours?

A

1-Antigens must be highly expressed on cancer cells, and absent on normal tissues
2-CAR-T cells are not trafficked into the centre of solid tumour masses
3-Tumour microenvironment suppresses T cell activity

36
Q

List some CAR-T side effects

A

Allergic reaction
Cytokine release syndrome
Neurological toxicity
Hyperuricemia

37
Q

What is Cytokine release syndrome?

A

AKA: Cytokine storm
(usually a sign CAR-T therapy has worked)

(CRS) is an acute systemic inflammatory syndrome characterized by fever and multiple organ dysfunction that is associated with chimeric antigen receptor (CAR)-T cell therapy,

38
Q

Describe Immune checkpoints and It’s purposes

A

Prevent the immune system ‘attacking’ normal cells.
Regulate the immune system

Checkpoint proteins on T cells bind to proteins on other cells, sending ‘on’ ‘off’ signals to T cells.

39
Q

What is CTLA-4?
(What does the acronym stand for?)

A

Cytotoxic T-lymphocyte-associated protein 4
It is homologous to CD28: both bind B7.1/2 on APCs

CTLA-4 has a greater affinity so outcompetes CD28
CTLA-4 transmits an inhibitory signal to T-cells
Whereas CD28 transmits stimulatory signals

40
Q

What is the difference between CTLA-4 and CD28?

A

CTLA-4 transmits an inhibitory signal to T-cells
Whereas CD28 transmits stimulatory signals

41
Q

What are Immune Checkpoint Inhibitors (ICIs)?

A

Blocks immune checkpoint binding
The lack of ‘off’ signal allows T cells to kill cancer cells
Immune checkpoint inhibitors work by blocking checkpoint proteins from binding with their partner proteins. This prevents the “off” signal from being sent, allowing the T cells to kill cancer cells.

42
Q

List examples of inhibitory immune checkpoints

A

CTLA-4
PD-1
PD-L1

43
Q

Describe Anti CTLA-4 mabs

A

Blocks B7.1/2 CTLA-4 binding > T cell activation > kills tumours

44
Q

What is PD-1?
Where is it found?

A

PD-1 is a cell surface receptor on T cells and B cells that has a role in regulating the immune system’s response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity.

T cells
B cells

45
Q

What is PD-L1?
Where is it found?

A

acts as “brake” to stop T cells, from attacking healthy cells.

Cancer cells
Dendritic cells
Macrophages
Natural killer cells
B cells
Epithelial cells

46
Q

Describe PD-1/PD-L1 binding?

A

PD/PD-L1 (if present on cancer cells) binding prevents T cells killing tumour cells

47
Q

What is highly expressed/upregulated on cancer cells?

A

PD-L1 is unregulated/overexpressed in cancer cells (tries to fight treatment)

48
Q

Give an example of an anti CTLA-4 mab, what it’s used for, its MOA and some side effects

A

Ipilimumab (Yervoy)
Use: melanoma , renal, colorectal cancer
MOA: blocks B7.1/2 CTLA-4 binding > T cell activation > kills tumours

49
Q

How do anti-PD-1 and PD-L1 mabs work?

A

Blocking PD/PD-L1 binding with (ICI) enables T cells to kill tumour

50
Q

Give 2 examples of anti-PD-1 mabs.
What diseases are they used in?

A

Nivolumab and Pembrolizumab
Used for melanoma, lung, head and neck, Hodgkin lymphoma

51
Q

Give an example of an anti PD-L1 mab.
What disease is it used in?

A

Atezolizumab
Used for lung and urothelial cancer

52
Q

List adverse effects of Immune checkpoint inhibitors (ICIs).

A

Gastrointestinal tract complications
Dermatological complications
Endocrine disorders
Myocarditis (Infrequent but highest fatality)

53
Q
A

Cytotoxic T cells recognise MHC class 1
Helper T cells recognise MHC class 2

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