Epigenetics and Immunotherapy Flashcards
What is epigenetics?
Epigenetics refers to the changes in gene expression that are not caused by changes in DNA sequence
What is methylation?
What is it?
Where does it occur?
What does it lead to?
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)
What is acetylation
Addition of acetyl group to the lysine residue of histone protein.
Leads to gene activation: separation of histones/DNA
What enzymes are responsible for methylation?
Explain their role(s)
DNMT1 - for the maintenance of methylation
DNMT3A
DNMT3B - both responsible for the methylation start process (De novo methylation process)
State the main therapeutic cancer epigenome targets (groups)
Broad spectrum reprogrammers
Narrow spectrum reprogrammers
Give examples of broad spectrum reprogrammers
DNMT1 inhibitors
HDAC inhibitors
What is DNMT1
The enzyme responsible for the maintenance of the methylation process
What cancer does DNMT1 inhibitors treat?
acute myelogenous leukaemia
DNMT1 inhibitor use, example, MOA and Side effects
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
What is HDAC
Histone deaceytlase, it induces chromatin closing
What are HATs
Histone acyetlation, induces chromatin opening
HDAC inhibitor example, MOA and side effects
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
what disease are HDAC inhibitors used in?
Breast cancer
Give examples of narrow spectrum reprogrammers
EZH2 inhibitors
What is EZH2
EZH2 is a catalytic component of PRC2
It catalyses the tri-methylation of histone H3 at lysine 27 (H3K27me3) to promote transcriptional silencing
What does EZH2 promote?
Cell survival, proliferation, invasion and drug resistance of cancer cells
Give an example of an EZH2 inhibitor
Tazemetostat
What does Tazemetostat treat?
Follicular lymphoma (subtype of B-cell cancer)
EZH2 has overexpression or mutation in FL
EZH2 inhibitor example, MOA and side effects
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
Define Immunotherapy?
Immunotherapy harnesses the body’s own immune system to prevent , control and eliminate cancer.
List the different Immune cells
Dendritic cells (DCs)
Macrophages
Natural Killer cells
B CELLS
Cytotoxic T cells
Helper T cells
List the cells part of the innate immune system
Dendritic cells (DCs)
Macrophages
Natural Killer cells
List the cells part of the adaptive immune system
B cells
Cytotoxic T cells
Helper T cells
Describe T cell activation
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
Name a cancer vaccine, what it’s used for, the MOA and its side effects
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
Name an oncolytic virus therapy, what it’s used for, the MOA and its side effects
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
Describe ‘man made’ cytokines, give examples and list 3 side effects
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)
What is Provenge (Sipuleucel-T)?
A cancer vaccine used in the treatment of advanced prostate cancer
What is T-VEC (Imlygic)?
An oncolytic virus therapy used in the treatment of melanomas
(modified herpes simplex virus)
Describe Adoptive cell transfer/T-cell therapy.
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
What is CAR-T cell therapy?
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
What is chimeric?
Combines antigen binding and T cell activating functions in one receptor
What can CAR-T therapy treat?
Describe the applications of CAR-T therapy.
Haematological malignancies
CD19 (….) is expressed in lymphomas (found in B cells) = most popular antigen target
BCMA (…) expressed in multiple myeloma = second popular target
What antigens/cells are popular CAR-T targets?
CD19…
BCMA…
Why isn’t CAR-T therapy effective for solid tumours?
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
List some CAR-T side effects
Allergic reaction
Cytokine release syndrome
Neurological toxicity
Hyperuricemia
What is Cytokine release syndrome?
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,
Describe Immune checkpoints and It’s purposes
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.
What is CTLA-4?
(What does the acronym stand for?)
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
What is the difference between CTLA-4 and CD28?
CTLA-4 transmits an inhibitory signal to T-cells
Whereas CD28 transmits stimulatory signals
What are Immune Checkpoint Inhibitors (ICIs)?
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.
List examples of inhibitory immune checkpoints
CTLA-4
PD-1
PD-L1
Describe Anti CTLA-4 mabs
Blocks B7.1/2 CTLA-4 binding > T cell activation > kills tumours
What is PD-1?
Where is it found?
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
What is PD-L1?
Where is it found?
acts as “brake” to stop T cells, from attacking healthy cells.
Cancer cells
Dendritic cells
Macrophages
Natural killer cells
B cells
Epithelial cells
Describe PD-1/PD-L1 binding?
PD/PD-L1 (if present on cancer cells) binding prevents T cells killing tumour cells
What is highly expressed/upregulated on cancer cells?
PD-L1 is unregulated/overexpressed in cancer cells (tries to fight treatment)
Give an example of an anti CTLA-4 mab, what it’s used for, its MOA and some side effects
Ipilimumab (Yervoy)
Use: melanoma , renal, colorectal cancer
MOA: blocks B7.1/2 CTLA-4 binding > T cell activation > kills tumours
How do anti-PD-1 and PD-L1 mabs work?
Blocking PD/PD-L1 binding with (ICI) enables T cells to kill tumour
Give 2 examples of anti-PD-1 mabs.
What diseases are they used in?
Nivolumab and Pembrolizumab
Used for melanoma, lung, head and neck, Hodgkin lymphoma
Give an example of an anti PD-L1 mab.
What disease is it used in?
Atezolizumab
Used for lung and urothelial cancer
List adverse effects of Immune checkpoint inhibitors (ICIs).
Gastrointestinal tract complications
Dermatological complications
Endocrine disorders
Myocarditis (Infrequent but highest fatality)
Cytotoxic T cells recognise MHC class 1
Helper T cells recognise MHC class 2
