dont know (6)

Question 1

L19- Cancer Vaccines?

Answer 1

• Therapeutic cancer vaccination against established diseases such as cancer
  has proven much more challenging, because the vaccine intervention must
  combat an immune system that has been suppressed (T cell exhaustion) by
  cancer and the immunosuppressive tumour microenvironment (TME)
• Major breakthrough – prevention of viral-induced cancer with a prophylactic
  vaccine. Recombinant synthetic vaccine against HPV is 100% effective in
  preventing cervical cancer by 2 key strains HPV-16 and HPV-18, which are
  associated with 70% of cervical cancers example of propolactic? Mentioned before. Need to know that. When targeting viruses linked to cancer.

hpv= virus linked to cervical cancer

Question 2

L19- Therapeutic cancer vaccines: challenge?

Answer 2

challenging as cancer can suppress t cells so response is sub-optimal. Might change with newer mrna vaccinations that might work.
The proportion of patients benefiting from treatment with therapeutic cancer vaccines,
in addition to the mean survival advantages, has been low to date
Reasons/challenges for therapeutic cancer vaccine failure include:
Suboptimal vaccine design to date, this will change with 3rd generation vaccine
approaches
and an immunosuppressive TME are the root causes of the lack of cancer eradication
(immune suppression driven by T cell exhaustion)

Challenges
Need to identify tumor (neo)antigens (next-generation sequencing)
Need to achieve sufficient antigen concentration in DCs
Need to consider:
Effective route of administration
DCs activation with adjuvants
Overcome tumor immunosuppression
Future - 3d generation DNA/RNA-based
Gene-based vaccine development?

Question 3

L19- Cancer Vaccines: Vaccines against nonviral antigens?

Answer 3

• Tumor antigens (neoantigens) (based on mutations of genes)
• Overexpressed antigens (overexpressed compared to normal cells)
  Strategies
• Ex vivo-generated DC vaccines:
  e.g. Provenge – fusion protein vaccine using the tumour antigen PAP (Prostate Acid
  Phosphatase) – differentiation antigen in prostate cancer

Sipuleucel-T (Provenge) cancer vaccine

Tumour antigen (Prostate Acid Phosphatase –PAP-) linked to a cytokine (GM-CSF) to help activate dendritic cells.
(1) Blood is collected from patient
(2) APCs are isolated
(3) APCs are incubated
(activated) with fusion protein- (tumour antigen)
of PAP-GM-CSF
(4) Activated/mature APC are
infused into the patient
(5) In vivo, APCs activate T
cells in patient
(6) Activated T cells in patient
recognise PAP tumour
antigen on prostate cancer
cells and attack the tumour
(T-cell mediated tumour
killing)
Sipuleucel-T
(Provenge), which is a cellular product based on enriched blood APCs that are
briefly cultured with a fusion protein of prostatic acid phosphatase (PAP) and
GM-CSF (stimulates DC cells, APCs) resulted in a significant prolonged median
survival in Phase III trials

Question 4

L19- Mode of action of therapeutic cancer vaccines.

Answer 4

Routes of vaccine administration and migration of
immune cells. Antigen-loaded DCs (APCs) travel
through the afferent lymph to the lymph nodes, where
they prime T cells. The primed, activated T cells
migrate through the efferent lymph, thoracic duct, and
blood to reach tumor cells
Vaccine-induced T cells must engage with and
overcome hostile elements in the cancer/tumour
microenvironment (TME), including
immunosuppressive cells (TRegs, MDSCs, inhibitory
fibroblasts) and factors released by the tumor cells,
such as immunosuppressive cytokines and IDO which
impair T cell migration, function, and expansion

Question 5

L19- cancer vaccines advantages for the future?

Answer 5

Cancer Vaccines – the near future
✓ Better results can most likely be obtained by a better choice of antigens,
improvements in vaccine design, and appropriate co-treatments*
✓ Combination immunotherapy (give vaccine that can bind with another drug) can alleviate immunosuppressive cancer
microenvironments and boost vaccine performance by appropriate
stimulation of the immune system
✓ Drugs treatments can mitigate the immunosuppressive cancer
microenvironment and include inhibitors of T cell checkpoints (immune
checkpoint blockade anti-PD-1, anti-PD-L1, anti-CTLA-4), agonists of
selected TNF receptor family members, and inhibitors of undesirable
Cytokines.

Question 6

L18- common methods of immune evasion (little detail)

Answer 6

Alter their structure/surface to hide from
host sensors e.g: altering the structure of their coating. Most can alter host defense mechanisms: * Inhibit cellular pathways e.g: proteins that translocate in cell and block production of inflammatory mediators?
* Damage/degrade host receptors
* Kill immune cells
* Also often activate and benefit from
inflammation
»Mediated by VIRULENCE FACTORS - proteins present only in pathogens.

Question 7

what are extracellular bacteria and immune mechanisms against them?

Answer 7

colonise the surface of barrier tissue
(gastrointestinal tract, respiratory
tract, skin) e.g: ecoli colonises the gut and causes diarrhoea
✓ Tissue spaces
✓ Blood - where they replicate efficiently

evasion:

• Epithelial barriers - physical barrier so help of innate with adaptive
• Antimicrobial peptides
• Complement
• Phagocytosis (macrophages, neutrophils)
• Neutrophil extracellular traps (NETs)
• Innate sensing and inflammation
• Antibodies
  Need mechanisms to work togethe

Question 8

evading antibody responses?

Answer 8

Antigenic variation: have diff mutations at the surface to not be recognised
Diff pillin cobmbinations to form pilli= difficult for antibodies to recognise them
Neisseria meningitidis
E. Coli
* Phase variation: change structure of lipopolysaccharides (LPS). downregulate the expression of proteins-phase variation.
Neisseria meningitidis
* Direct degradation of Ab (IgA protease)
Neisseria meningitidis
H. influenzae
Streptococcus pneumoniae

Question 9

L18- disrupting epithelial barriers, COMPLEMENT AND NETS and phagocytosis?

Answer 9

Epithelial barriers are first line of defense and
first obstacle for pathogens which have
evolved mechanisms for
* Direct destruction of tight junctions
(Enteropathogenic E.coli - EPEC)
* Induction of inflammation

TARGETING COMPLEMENT

• Mimicking host proteins - CD59-like (negative regulator of complement, prevent mac assembly), B burgdorferi, hijacks negative regulator. ?
• Hijacking negative regulators – Factor H - Neisseria meningitidis
• Secretion of proteases – C3/C5 cleavage, P aeruginosa
• Secretion of evasion molecules - C3/C5 inhibition, S aureus

NETs
* Regulated explosion of
neutrophils
* DNA coated with histones and
chromatin>TRAP
* Enzymes/antimicrobial proteins:
neutrophil elastase
myeloperoxidase» KILL
inhibition of release e.g: induction of host IL-10, degradation e.g: nucleases, resistance e.g: encapsulation, resistance proteins e.g: M1. all done by diff bacteria.
To dna trap or inhibit enzymes
Nets more efficient against single bacteria, forming colony makes it harder for nets to attack.

Phagosome fuses with lysosome to form
phagolysosome where bacteria are killed
Evasion by extracellular pathogens
* Inhibition of phagocytosis
- Blocking actin polymerization
Yersinia, EPEC, Pseudomonas: have evolved inhibitors of actin pol
* Hiding from Complement or Antibodies by expressing sugary coat: Capsule
Prevention of killing
- Inhibition of ROS
- Staph (Catalase)
* Direct killing of innate immune cells
> regulated activation of apoptosis: EPEC,
Yersinia
> toxins: Staph

Question 10

evading PRRS?

Answer 10

PRRs initiate immune responses by recognizing PAMPs, leading to the upregulation of pro-inflammatory cytokines, which:
Recruit and activate other immune cells.
Trigger signaling cascades to control infections.
Pathogen Evasion Strategies:

Pathogens have evolved mechanisms to evade detection and block immune responses, such as:
Blocking PRR activity (e.g., receptor inhibition).
Inhibiting kinase signaling pathways downstream of PRRs.
Preventing the activation or nuclear entry of transcription factors needed for inflammatory responses.
Blocking or degrading inflammatory mediators.
Interferons (IFNs):

Interferons are critical for protecting tissues from infection by inducing an antiviral state and enhancing immune responses.
They are produced in response to PRR activation and trigger the expression of interferon-stimulated genes (ISGs) that inhibit pathogen replication.
Pathogen Strategies to Evade IFN Responses:

Pathogens, such as Francisella, can evade inflammatory signaling by:
Modifying PAMPs to avoid detection by PRRs.
Blocking various components of inflammatory signaling, including:
Receptors: Preventing PAMP recognition.
Signaling Components: Inhibiting downstream pathways.
Transcription Factors: Blocking their activation or nuclear translocation.
Inflammatory Mediators: Inducing degradation or inhibition to suppress the immune response.
Impact of Evasion Strategies:

By disrupting these key processes, pathogens can avoid immune detection and enhance their survival within the host.