Module 2 Flashcards
(42 cards)
1
Q
Causes of melanoma
A
- sunburn
- skin type
- slight genetic association
2
Q
6 hallmarks of cancer
A
- sustaining proliferative signalling
- evading growth suppressors
- activating invasion and metastasis
- enabling replicative immortality
- inducing angiogenesis
- resisting cell death
ALL MEDIATED VIA MANY PROTEIN CHANGES
3
Q
common mutants in melanoma
A
- b-raf
- if not b-raf than usually N-ras or c-kit
- mutually exclusiv
4
Q
Treatment options for melanoma
A
- prevention
- early detection and surgery
- chemotherapy and radiotherapy = kinase inhibitors and cytotoxics
- immunotherapy
5
Q
T cells
A
- white blood cells that kill cancer cells
- CD8+ (CTL)
- CD4+ (helpers)
6
Q
How do CTL kill virus-infected cells
A
- via perforin and granzymes or TNF
- perforin inserts into the target cell membrane forming channels to allow granzymes to enter and trigger cell death via activation of caspases
- may also kill via TNF-family ligands that bind to receptors on the cell surface inducing cell deaths
- also causes cytokine release which is proinflammatory and anti-angiogenic
7
Q
CTL recognition mechanism
A
- antigen is created via the breakdown of pathogenic proteins using the proteasome
- fragments bind to the MHC class I molecules
- MHC class I molecules are then moved from the endoplasmic reticulum to the surface of the cell via vesicles
- TCR binds and recognises the antigen presented
8
Q
What can melanoma antigens be derived from
A
- mutant proteins such as b-raf
- newly expressed proteins which have never been seen before such as NY-ESO-1
- over-expressed protein
9
Q
Advantages of different classes of proteins that are targeted in melanoma
A
- some melanoma targe proteins are shared by different patients
- some melanoma target proteins are also found in other cancers
10
Q
disadvantages of different classes of proteins that are targeted in melanoma
A
- some melanoma target proteins expressed by normal cells
- some targets are unique to individual patients
11
Q
Structure aspect of TCR allowing them to bind a wide range of antigens
A
have diversity within their variable regions
12
Q
Adoptive immunotherapy
A
- growing CTL and infusing them
- lymphodepletion done prior to improve CTL survival and proliferation in vivo and clinical efficacy
- 3 main forms = tumour infiltrating lymphocyte therapy, engineered TCR therapy, CAR T cell therapy
13
Q
Tumour infiltrating lymphocyte therapy
A
- harvests naturally occurring T cells that have already infiltrated patients tumours
- activated and expanded then re-infused into patients
14
Q
Engineered TCR therapy
A
- harvest T cells from patients and engineer a new TCR enabling them to target specific cancer antigens
- these are then activated and expanded prior to infusion
15
Q
CAR T cell therapy
A
- equip a patients T cells with a synthetic receptor known as chimeric antigen receptor (CAR)
- CAR can bind to cancer cells even if the antigens arent presented on the surface via MHC
16
Q
Advantages of adoptive immunotherapy
A
- direct
- applicable to other diseases not just cancer
17
Q
Disadvantages of adoptive immunotherapy
A
- in the past producing T cells took too long but now there are new rapid protocols
- older protocols produced relatively few tumour-specific T cells
- CTL lifespan too short after infusion
- very complex
18
Q
Therapeutic vaccine
A
- given after cancer starts so it is not preventative
- different technologies to stimulate T cell antibodies = viral vectors, peptide tech and mRNA
- targeted at specific molecules
- MAGE3/HLA-A1 = first molecularly targeted vaccine that induced therapeutic response but it did not strongly stimulate CTL
19
Q
Therapeutic vaccine advantages
A
- practical for mass use
- can use in early disease
- good safety profile so it is easy to combine with other therapies
20
Q
Therapeutic vaccine disadvantages
A
- most clinical trials results showed only a minority responding
- in the past CTL induced have easily been defeated y immune checkpoints but now checkpoint blockers can be used
21
Q
Immune modulators
A
- encourage spontaneous CTL responses
- checkpoint blockades such as PD-1 and CTLA-4
- blocks normal immune control mechanisms in the immune system so it can result in autoimmune side effects
- some patients have cold tumours so they need a T cell stimulator
22
Q
PD-1 and anti PD-1
A
- when PD-1 is bound to PD-L1 it prevents T cells from killing cancer cells
- When unbound then T cells can kill cancer cells
- cancer cells manipulate this to make it always bound
- anti PD-1 block this allowing T cells to be released = increased cancer cell death
- anti pd-1 isnt effective in all patients due to other stop buttons and sometimes its a cold tumour
23
Q
CTLA-4
A
when CTLA-4 is bound to B7 it prevents T cells from killing cancer cells
24
Q
Oncolytic therapy
A
- viruses that can only replicate within cancer cells
- replication of the virus causes tumour cells to burst leading to the release of cell contents exposing them to the immune system
25
Forms of immunotherapy
- adoptive
- therapeutic vaccine
- immune modulators
- oncolytic therapy
26
Different types of melanoma antigens
- Tumour-specific antigens/neoantigens = unique to melanoma cells, targeting minimises attack on healthy tissues
- Cancer-Testis Antigens = NY-ESO-1/MAGE-A3, expressed in melanoma and testes > potential for autoimmunity
- Overexpressed antigens = gp100, high therapeutic benefit but are expressed in normal cells so could cause damage to healthy tissues
27
Why PD-1 targeting drugs dont benefit all patients
- Cold tumours
- Loss of MHC-1 expression is common in melanoma = no T-cell recognition
- Alternative immune checkpoints
28
How to overcome PD-1 resistance
- Combine with CTLA-4 blockade > Postow et al. 2015
- Combine with LAG-3 inhibitor > Tawbi et al. 2022
- Used personalised neoantigen vaccines to make the tumour more visible to T cells
- Combine with adoptive cell therapy
29
What cells express PD-L1
- Tumour cells upregulate PD-L1 to evade immune attack
- Antigen presenting cells
- Non-immune cells
30
Molecular signals that trigger PD-L1 expression
- Inflammatory cytokines (IL-10, IL-1, TNF-a) induced via the JAK/STAT, MAPK and AKT pathways
- Toll like receptor signalling on APCs
31
Other PD-1 ligands
- Dong et al. 2016
- PD-L2
- Has a more limited expression > mostly in APC not immune cells such as T cells
32
What cells express PD-1
- Activated T cells
- Regulatory T cells
- B cells
33
Molecular signals that trigger PD-1 expression
- TCR activation
- Cytokine signalling > IFN and IL
34
Role of PD-1 in a healthy immune system
- Prevents autoimmunity by inhibiting self-reactive T cells
- Limits immune responses = reduced inflammation
35
Therapeutic benefits of PD-1 inhibitors
- durable responses
- improved survival
- long term control
- can be used with other therapies such as CTLA-4 inhibitors or with vaccines
36
Side effects of anti-PD-1
- Immune related adverse events = rash, gastro effects
- fatigue
37
What long term impact do anti-PD-1 therapies have on patients lives
- prolonged survival
- improved quality of life
38
Source of CTL for TIL
- melanoma tumour tissue
- tumours fragments are digested and cultured in IL-2 to expand
- selected via IFN-y secretion assays
39
TCR and CAR-T source
- patient peripheral blood mononuclear cells
- TCR = transduced with tumour specific TCR
- CAR-T = engineered with a chimeric antigen receptor targeting melanoma surface antigen
- expanded with IL-2
40
Why were vaccine responses limited pre-2010
- Targeted self antigens which led to immune tolerance
- Used non patient specific antigens
- did not lymphodeplete prior
- Lack of combination with CPI
41
Improvements in vaccines
- neoantigen = patient specific = enhanced immunogenicity
- combination with CPI such as fixvac with ipi > Sahin et al. 2020
- improved delivery platforms such as mRNA vaccines = FixVac which improve antigen presentation
42
Benefits of mRNA vaccine technology
- personalised neoantigen vaccines
- can be combined with checkpoint inhibitors
- LNP used to efficiently deliver to dendritic cells
- need long term memory T cells
