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I&I WC2 > Oncolytic viruses > Flashcards

Oncolytic viruses Flashcards

Lectures Friday 10-1

1
Q

How many percent of oncolytic viruses have been marketed?

A

~1-2%

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2
Q

What is the top three of cancer types that are the focus of oncolytic viral therapy?

A
  1. Melanoma
  2. Lung cancer
  3. Glioma
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3
Q

Why are melanoma, lung cancer and glioma the most studied cancer types in oncolytic viral therapy?

A

They are most immunogenic

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4
Q

What kind of oncolytic virus is T-vec and what does it encode for?

A

HSV-1 -> encodes for GM-CSF

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5
Q

How is local oncolytic viral therapy performed?

A

Tumor is resected -> inject virus on the site of surgery

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6
Q

What are the three applications of oncolytic viruses?

A
  1. Kills tumor cells
  2. Makes tumor cells visible to immune system
  3. Activates immune system
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7
Q

What encompasses the 2-step mechanism of oncolytic viral therapy?

A
  1. Local effect -> tumor cell lysis
  2. Systemic effect -> tumor-specific immune response
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8
Q

Which factors are part of the first step (local effect) of oncolytic viral therapy? (2)

A
  1. Selective viral replication in tumor tissues
  2. Tumor cells rupture for an oncolytic effect
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9
Q

Which factors are part of the second step (systemic effect) of oncolytic viral therapy? (2)

A
  1. Systemic tumor-specific response -> triggering phagocytosis
  2. Death of distant cancer cells (CD8+ T cells)
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10
Q

Using OV-GFP to infect cancer cells, what do you see when you coculture these infected cells with macrophages?

A

Phagocytosis of the infected cells

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11
Q

Which oncolytic viruses are currently in clinical development? (9)

A
  1. Adenovirus
  2. HSV1
  3. Vaccina virus
  4. Myxoma virus
  5. Reovirus
  6. Poliovirus
  7. VSV
  8. MW
  9. NDV
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12
Q

When considering tumor selectivity, which two virus types exist?

A
  1. Oncotropic viruses
  2. Genetically engineered viruses
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13
Q

On what is tumor specificity based with oncotropic viruses?

A

Conditions of the tumor microenvironment which favor viral replication and/or immune evasion

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14
Q

Oncotropic/genetically engineered viruses can be administered systemically

A

Oncotropic

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15
Q

Which alterations are introduced in genetically engineered viruses? (2)

A
  1. Deletions/mutations in viral genes essential for replication in non-malignant cells
  2. Insertion of tumor-specific promotors driving viral replication
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16
Q

What are the characteristics of a glioblastoma? (4)

A
  1. Infiltrative growth
  2. BBB
  3. Intrinsic drug resistance
  4. Heterogeneity
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17
Q

What is Delta24-RGD?

A

Oncolytic viruses -> modified adenovirus DNA genome

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18
Q

Which modifications are present in Delta24-RGD? (2)

A
  1. 24 base pair deletion
  2. RGD-4C insertion
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19
Q

What are the functions of the 24 base pair deletion in Delta24-RGD? (2)

A
  1. Safety
  2. Restricts virus replication to tumor cells
20
Q

What are the functions of the RGD-4C insertion in Delta24-RGD? (2)

A
  1. Efficacy
  2. Enhances tumor cell infection via integrins
21
Q

Describe the mechanism of action of a wildtype adenovirus in a normal cell (3)

A
  1. Virus enters cell in G1 phase and makes E1A
  2. E1A binds retinoblastoma which releases E2F (TF)
  3. E2F induces cell cycle
22
Q

Describe the mechanism of action of Delta24 adenovirus in a normal cell (3)

A
  1. E1A can’t bind retinoblastoma
  2. Cell is not pushed to cell cycle
  3. No viral replication
23
Q

Describe the mechanism of action of Delta24 adenovirus in a cancerous cell (3)

A
  1. Virus enters cancer cell
  2. Virus doesn’t need to bind RB, because E2F is freely available
  3. Virus can only replicate in tumor cells with aberrant pathway
24
Q

How can you determine the tumor selectivity of a virus?

A

Add virus to a tumor line and see whether it is oncolytic and to what extent

25
Q

Describe the experimental options of a heterotopic subcutaneous pre-clinical study (2)

A
  1. Xenograft/immune-deficient + human tumor
  2. Syngenic/immune competent + human tumor
26
Q

True or false: regression of tumor volume after injection of an oncolytic virus was observed in immune deficient mice

27
Q

Which substance has been used to study the involvement of the immune system in oncolytic viral therapy?

A

Dexamethasone

28
Q

Describe the experimental options of a orthotropic (intracranial) pre-clinical study

A
  1. Virus only
  2. Virus + dexamethasone
  3. Dexamethasone only
29
Q

True or false: When studying the involvement of the immune system (oncolytic virus + dexamethasone), you have to use immune deficient mice

A

False -> immune competent mice are required

30
Q

What happens to the effect of the virus when used in combination with dexamethasone?

A

You loose the effect of the oncolytic virus

31
Q

What is meant with “long-term memory” in the orthotropic (intracranial) preclinical model?

A

If you rechallenge the mice survivors -> they don’t grow tumors again

32
Q

What is a problem when studying adenoviruses for oncolytic viral therapy?

A

Adenoviruses are species specific

33
Q

Which animal species is (semi) permissive to human adenovirus?

A

Cotton rats

34
Q

Which parameters are important to consider for translation purposes in an intracranial cotton rat experiment? (3)

A
  1. Toxicity of the injection
  2. Biodistribution of virus -> leakage to other organs
  3. Excreta analysis -> shedding of virus
35
Q

True or false: Glioblastoma subtypes have similar sensitivity or resistance levels against oncolytic viruses

A

False. This is a rather broad spectrum

36
Q

True or false: If a tumor is resistant to a certain oncolytic virus, it will also be resistant to other oncolytic viruses

A

False. Tumors that are very resistant to 1 virus, could (in some cases) be very sensitive to another virus

37
Q

Which parameter is indicative of a high sensitivity of the tumor to the oncolytic virus?

A

Higher amounts of virus in the CSF

38
Q

Which parameters do you need to consider for clinical application of oncolytic viral therapy? (5)

A
  1. Delivery
  2. Treatment schedule
  3. Patient group
  4. Safety
  5. Trial-associated
39
Q

What are the delivery options for clinical application of oncolytic viral therapy? (4)

A
  1. Systemic
  2. Local
  3. Injections
  4. Infusions
40
Q

Which two patients groups exist for oncolytic viral therapy?

A
  1. Primary
  2. Recurrent
41
Q

Why is it not necessary to infect every single tumor cell with oncolytic virus?

A

The immune system is able to kill leftover tumor cells

42
Q

What avenue would be interesting to investigate in the future for OV?

A

Personalized OV therapy

43
Q

What can happen if a patient has pre-existing immunity against adenoviruses?

A

Cytokine storm

44
Q

What are the requirements for production platforms in oncolytic viral therapy? (3)

A
  1. High yields
  2. High purity
  3. Product consistency
45
Q

What is meant with a “suicide gene”?

A

The introduction of a viral gene into tumor cells -> convert a non-toxic pro-drug to a toxic one

46
Q

What are two approaches to modify an oncolytic vaccinia virus?

A
  1. Deglycosylation
  2. TRIF transgene

I&I WC2 (16 decks)

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