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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
Q

What is a challenge of performing animal experiments with adenoviruses?

A

Adenoviruses are species-specific -> human oncolytic viruses might not be able to infect animals

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26
Q

How can human adenoviruses still infect mice, despite the species-specificity of these viruses?

A

Using immune-deficient mice

27
Q

What does ‘heterotopic’ tumour xenograft location mean?

A

In another location than where it normally occurs (for instance subcutaneous, intraperitoneal)

28
Q

What does ‘orthotopic’ tumour xenograft location mean?

A

Xenograft in the same location where the tumour normally occcurs

29
Q

The immune system [does/does not] play an important role in tumour lysis in animal experiments of Delta24-RGD

A

The immune system does play an important role

30
Q

What is the effect of dexamethasone on oncolytic virotherapy using Delta24-RGD? Why is this potentially problematic?

A

It reduces oncolytic virotherapy efficiency

Problematic because dexamethasone is often given to decrease symptoms of intracranial tumours

31
Q

[CD4+/CD8+/both] are important for efficient lysis by oncolytic virotherapy

A

Both CD4+ and CD8+ T-cells are required for an efficient response

32
Q

True or false: trace amounts of Delta24-RGD can be found in bodily excreta during intracranial treatment

A

False: no excretion of virus -> important for environmental safety

33
Q

True or false: after intracranial administration of Delta24-RGD, it can distribute to other organs

A

False: the virus shows no biodistribution

34
Q

What are important considerations when running a trial with oncolytic virotherapy? (5)

A
  1. Delivery
  2. Treatment schedule
  3. Patient selection/group
  4. Safety
  5. Follow-up & sampling
35
Q

What is the first step in a clinical trial of oncolytic virotherapy?

A

Dose escalation study

36
Q

What is the most important safety precation when treating patients with Delta24-RGD virotherapy?

A

Isolated care to prevent spreading of the virus into the environment

37
Q

Why is wound fluid leakage an especially dangerous adverse effect when administering virotherapy?

A

This could lead to leakage into the environment

38
Q

True or false: Delta24-RGD virotherapy was successful in the majority of patients in clinicals trials

A

False (succes rate 2/19)

39
Q

What are the immunological findings in patients after administration of oncolytic virotherapy?

A
  1. Increased levels of T- and NK-cell subsets in CSF
  2. Cytokine responses of TNF-α & IFN-γ
40
Q

What determines the level of cytokine response after administration of oncolytic virotherapy?

A

Amount of viral particles detected

41
Q

Patients treated with Delta24-RGD with a [low/high] [TNF-α, /IFN-γ] show a better response

A

High IFN-γ = better response

42
Q

Which strategies can be employed to improve future oncolytic virotherapy treatment? (5)

A
  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
Q

Why can personalized OV treatment lead to better succes?

A

It might increase the response rate by determining which patients/tumours are susceptible to which viruses

44
Q

What is a major challenge for mass introduction of oncolytic virotherapy?

A

Production of viruses: no production platform with high yields & purity

45
Q

Which features do production facilities for oncolytic virotherapy need to have? (4)

A
  1. High yields
  2. High purity
  3. Product consistency
  4. Genetic stability of virus
46
Q

Why are DNA viruses possibly more useful as oncolytic virotherapy than RNA viruses?

A

DNA viruses are more stable

47
Q

What are the three major biological challenges for oncolytic viruses?

A
  1. Tumour heterogeneity
  2. Balancing anti-tumour & anti-virus immunity
  3. Delivery of viruses to tumours
48
Q

What is the main reason that oncolytic virotherapy has a low response rate in clinical trials?

A

Tumour heterogeneity

49
Q

What is needed to personalize OV treatment?

A

Good biomarkers to stratify patients for treatment with different viruses

50
Q

Which two biomarkers are in development to test tumour susceptibility to OVs?

A
  1. Linking molecular prolifes of tumours to sensitivity to particular OVs
  2. Pre-screening oncolytic viruses on patient tumour culture
51
Q

Which strategies can be employed to point the immune response against OVs towards anti-tumour responses? (3)

A
  1. Arming OVs with immune-stimulating factors
  2. Shift respones from anti-viral to anti-tumour
  3. Prime-boosting using multiple different viruses
52
Q

How can an immune be shifted from anti-viral to anti-tumour?

A

Modify viruses to prevent TLR2 activation and to stimulate TLR3 activation

53
Q

What is the result of TLR2 activation? Why is this unwanted in oncolytic virotherapy?

A

TLR2 generates anti-viral antibody response -> no anti-tumour effect

54
Q

What is the result of TLR3 activation? Why is this desired in oncolytic virotherapy?

A

Induces cellular response -> can attack tumours

55
Q

How can TLR3 pathway activation by oncolytic viruses be achieved? (2)

A
  1. Deglycosylation of the virus
  2. Expression of TRIF transgene
56
Q

What is the rationale of prime-boosting oncolytic virotherapy using different viruses?

A

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
Q

What are the immunological effects of prime-boosting strategies in oncolytic virotherapy? (4)

A
  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
Q

True or false: the response to oncolytic virotherapy is correlated to the percentage of tumour cells infected by the oncolytic virotherapy

A

True (shows that the immune response alone is often insufficient)

59
Q

What are possible strategies for improved delivery of oncolytic virotherapy?

A
  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. Packaing OVs in extracellular vesicles/exosomes
60
Q

How can viruses be modified to target tumour cells? (2)

A
  1. Coupling molecules after virus production, such as bispecific antibodies
  2. Genetically modifying the virus by fusing targeting structures
61
Q

How can adenoviruses be modified to prevent clearance by liver cells?

A

Mutating viral capsid proteins

62
Q

Which blood-borne and non-human viruses are currently being investigated for systemic delivery of oncolytic virotherapy? (4)

A
  1. Measles virus
  2. Poliovirus
  3. Newcastle Diease Virus (NDV)
  4. Non-human type adenovirus
63
Q

Why does packaging OVs in exsomes increase delivery efficiency?

A

These can deliver contents deep into tissues

I&I WC2 (18 decks)

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