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I&I WC2 > Oncolytic viruses > Flashcards

Oncolytic viruses Flashcards

1
Q

What is a characteristic in tumour that is beneficial for oncolytic virotherapy? Why?

A

High mutation load -> high immmunogenicity

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2
Q

What are tumours with a high mutation load? (2)

A
  1. Melanoma
  2. Lung cancer
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3
Q

Which two tumour characteristics are the two main reasons to develop oncolytic virotherapy?

A
  1. High mutation load
  2. No current treatment available
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4
Q

What was the first marketed oncolytic viral therapy?

A

T-Vec

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5
Q

What was the target tumour of T-Vec?

A

Melanoma

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6
Q

What virus was used in T-Vec? How was it modified?

A

Oncolytic HSV1 encoding GM-CSF

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7
Q

What are the three goals of virotherapy?

A
  1. Kill tumour cells
  2. Make tumour cells visible to the immune system
  3. Activate the immune system
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8
Q

Oncolytic virotherapy is a two-step process. What are the steps?

A
  1. Infecting tumour cells -> cell lysis
  2. Lysis releases DAMPs & tumour-derived antigens -> immune attack on tumour
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9
Q

What are two important characteristics that an oncolytic virus must possess?

A
  1. Tumour selectivity
  2. Arming must be possible
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10
Q

What is an oncotropic virus?

A

A virus with tumour specificity based on the conditions in the tumour/tumour environment that favour viral replication & immune evasion

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11
Q

Which two options are there to genetically engineering tumour-specificity into oncolytic viruses?

A
  1. Deletions/mutations in viral genes that are essential for replication in non-malignant cells
  2. Insertion of tumour-specific promotors for viral replication
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12
Q

What is “arming” of oncolytic viruses?

A

Encoding cytotoxic/immune-stimulating transgenes

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13
Q

True or false: glioblastoma is a rare kind of brain tumour

A

False: glioblastoma is the most frequently occurring brain tumour in adults

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14
Q

What is the most commonly diagnosed type of glioblastoma?

A

Grade IV -> aggressive form

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15
Q

What is the current prognosis of grade IV GBM (=glioblastoma)?

A

Very poor (<15 months)

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16
Q

Which features of grade IV GBM lead to a poor prognosis? (3)

A
  1. Infiltrative growth -> complete resection impossible
  2. Located behind blood-brain barrier -> hard to target with drugs
  3. Cells are intrinsically resistant to chemo- and radiotherapy
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17
Q

What kind of virus is Delta24-RGD?

A

Adenovirus

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18
Q

What modification has been made to Delta24-RGD to make it tumour-specific?

A

Deletion in the E1A gene

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19
Q

How do WT adenoviruses normally replicate, using their E1A gene?

A

E1A binds to Rb-protein -> releases E2F transcription factor -> replication

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20
Q

How does the Δ24 mutation of Delta24-RGD block replication in healthy cells?

A

E1A can no longer bind Rb -> induction of cell cycle blocked

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21
Q

Why is replication of Delta24-RGD still possible in tumour cells?

A

These have a mutated Rb-pathway (no need for E1A) -> cell cycle is continuously active -> efficient viral replication in tumour cells

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22
Q

In addition to the Δ24 mutation, Delta24-RGD also has a RGD-4C insertion. What is its function?

A

Enhances tumour cell infiltration via integrins that are highly expressed on tumour cells

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23
Q

Which two modifications does Delta24-RGD carry? What are their functions?

A
  1. E1A Δ24 mutation -> tumour specificity
  2. RGD-4C insertion -> higher entry into tumour cells (arming)
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24
Q

Which two kinds of experiments need to be performed in vitro before an oncolytic virus can be progressed to in vivo research?

A
  1. Cell line experiments to show tumour specificity & lysis
  2. Tumour organoids to show virus penetration in solid structures
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25
What is a challenge of performing animal experiments with adenoviruses?
Adenoviruses are species-specific -> human oncolytic viruses might not be able to infect animals
26
How can human adenoviruses still infect mice, despite the species-specificity of these viruses?
Using immune-deficient mice
27
What does 'heterotopic' tumour xenograft location mean?
In another location than where it normally occurs (for instance subcutaneous, intraperitoneal)
28
What does 'orthotopic' tumour xenograft location mean?
Xenograft in the same location where the tumour normally occcurs
29
The immune system [does/does not] play an important role in tumour lysis in animal experiments of Delta24-RGD
The immune system does play an important role
30
What is the effect of dexamethasone on oncolytic virotherapy using Delta24-RGD? Why is this potentially problematic?
It reduces oncolytic virotherapy efficiency Problematic because dexamethasone is often given to decrease symptoms of intracranial tumours
31
[CD4+/CD8+/both] are important for efficient lysis by oncolytic virotherapy
Both CD4+ and CD8+ T-cells are required for an efficient response
32
True or false: trace amounts of Delta24-RGD can be found in bodily excreta during intracranial treatment
False: no excretion of virus -> important for environmental safety
33
True or false: after intracranial administration of Delta24-RGD, it can distribute to other organs
False: the virus shows no biodistribution
34
What are important considerations when running a trial with oncolytic virotherapy? (5)
1. Delivery 2. Treatment schedule 3. Patient selection/group 4. Safety 5. Follow-up & sampling
35
What is the first step in a clinical trial of oncolytic virotherapy?
Dose escalation study
36
What is the most important safety precation when treating patients with Delta24-RGD virotherapy?
Isolated care to prevent spreading of the virus into the environment
37
Why is wound fluid leakage an especially dangerous adverse effect when administering virotherapy?
This could lead to leakage into the environment
38
True or false: Delta24-RGD virotherapy was successful in the majority of patients in clinicals trials
False (succes rate 2/19)
39
What are the immunological findings in patients after administration of oncolytic virotherapy for glioblastoma? (2)
1. Increased levels of T- and NK-cell subsets in CSF 2. Cytokine responses of TNF-α & IFN-γ
40
What determines the level of cytokine response after administration of oncolytic virotherapy?
Amount of viral particles detected
41
Patients treated with Delta24-RGD with a [low/high] [TNF-α, /IFN-γ] show a better response
High IFN-γ = better response
42
Which strategies can be employed to improve future oncolytic virotherapy treatment? (5)
1. Arm OVs with cytotoxic genes/immune-stimulatory genes 2. Combine OVs with enhancing agents 3. Combine OVs with other immunotherapies 4. Combining multiple OVs 5. Personalize OV treatment
43
Why can personalized OV treatment lead to better succes?
It might increase the response rate by determining which patients/tumours are susceptible to which viruses
44
What is a major challenge for mass introduction of oncolytic virotherapy?
Production of viruses: no production platform with high yields & purity
45
Which features do production facilities for oncolytic virotherapy need to have? (4)
1. High yields 2. High purity 3. Product consistency 4. Genetic stability of virus
46
Why are DNA viruses possibly more useful as oncolytic virotherapy than RNA viruses?
DNA viruses are more stable
47
What are the three major biological challenges for oncolytic viruses?
1. Tumour heterogeneity 2. Balancing anti-tumour & anti-virus immunity 3. Delivery of viruses to tumours
48
What is the main reason that oncolytic virotherapy has a low response rate in clinical trials?
Tumour heterogeneity
49
What is needed to personalize OV treatment?
Good biomarkers to stratify patients for treatment with different viruses
50
Which two biomarkers are in development to test tumour susceptibility to OVs?
1. Linking molecular prolifes of tumours to sensitivity to particular OVs 2. Pre-screening oncolytic viruses on patient tumour culture
51
Which strategies can be employed to point the immune response against OVs towards anti-tumour responses? (3)
1. Arming OVs with immune-stimulating factors 2. Shift respones from anti-viral to anti-tumour 3. Prime-boosting using multiple different viruses
52
How can an immune response be shifted from anti-viral to anti-tumour?
Modify viruses to prevent TLR2 activation and to stimulate TLR3 activation
53
What is the result of TLR2 activation? Why is this unwanted in oncolytic virotherapy?
TLR2 generates anti-viral antibody response -> no anti-tumour effect
54
What is the result of TLR3 activation? Why is this desired in oncolytic virotherapy?
Induces cellular response -> can attack tumours
55
How can TLR3 pathway activation by oncolytic viruses be achieved? (2)
1. Deglycosylation of the virus 2. Expression of TRIF transgene
56
What is the rationale of prime-boosting oncolytic virotherapy using different viruses?
Multiple different vectors targeting the same antigen lead to an immune response mainly focussed on the antigen, and not a 50/50 response between virus & antigen
57
What are the immunological effects of prime-boosting strategies in oncolytic virotherapy? (4)
1. Higher number of antigen-specific CD8+ T-cells 2. Higher avidity of CD8+ T-cells 3. Increased T-cell functionality (more cytokines/granzyme B) 4. Increased T-memory formation
58
True or false: the response to oncolytic virotherapy is correlated to the percentage of tumour cells infected by the oncolytic virotherapy
True (shows that the immune response alone is often insufficient)
59
What are possible strategies for improved delivery of oncolytic virotherapy? (4)
1. Modification of the virus to target tumour cells 2. Modify the virus to prevent clearance by liver cells 3. Using blood-borne viruses/non-human viruses for systemic delivery 4. Packaging OVs in extracellular vesicles/exosomes
60
How can viruses be modified to target tumour cells? (2)
1. Coupling molecules after virus production, such as bispecific antibodies 2. Genetically modifying the virus by fusing targeting structures
61
How can adenoviruses be modified to prevent clearance by liver cells?
Mutating viral capsid proteins
62
Which blood-borne and non-human viruses are currently being investigated for systemic delivery of oncolytic virotherapy? (4)
1. Measles virus 2. Poliovirus 3. Newcastle Disease Virus (NDV) 4. Non-human type adenovirus
63
Why does packaging OVs in exosomes increase delivery efficiency?
These can deliver contents deep into tissues

I&I WC2 (25 decks)

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