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Therapeutic vaccination Flashcards

1
Q

What is the cancer immunotherapy cycle?

A
  1. Release of tumour antigens due to tumour cell lysis
  2. Antigen taken up by DCs
  3. DCs instruct T-cells to become more activated & attack tumour
  4. T-cells attack tumour and cause more lysis
  5. More DC activation -> cycle
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2
Q

At which stages can the cancer immunotherapy cycle be targeted?

A

All stages

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3
Q

What is the role of DC vaccines in the cancer immunotherapy cycle?

A

Aim: to kickstart the immunotherapy cycle by loading DCs with tumour antigen

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4
Q

What is the biggest difference between prophylactic vaccines (against infectious diseases) and therapeutic vaccines?

A

Prophylactic vaccines often aim for a humoral response, therapeutic vaccines for a cellular response

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5
Q

In which settings can therapeutic vaccines be used?

A
  1. Cancer: start/boost cancer immunotherapy cycle
  2. Chronic infections: overcome exhaustion
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6
Q

Which cells are used as APCs in therapeutic vaccination? Why?

A

DCs -> able to present internalized antigens on MHCI (cross-presentation) & MHCII -> induces strong CD4+ and CD8+ T-cell response

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7
Q

Which two antigen presentation pathways do DCs have?

A
  1. Cross-presentation
  2. Regular presentation
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8
Q

Where are antigens that are presented on MHCI usually derived from?

A

Proteins in the cytosol

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9
Q

How are proteins in the cytosol processed for presentation on MHCI? (2)

A
  1. Degradation in proteasome
  2. Loading onto MHCI in the ER
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10
Q

How can external antigens be presented on MHCI? (2)

A

Cross-presentation:
1. Migration of externally derived proteins to the proteasome, where they enter the cytosolic pathway
2. Exchance of peptides in the endosome -> MHCI internalized with the endosome and loaded with external proteins

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11
Q

Why is cross-presentation an important feature of any APC used in therapeutic vaccination?

A

A potent CD8+ T-cell response needs to be induced

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12
Q

How are externally-derived proteins loaded onto MHCII?

A
  1. Endocytosed antigens are degraded in the endosome
  2. The endosome contrains MHCII complexes which can be directly loaded
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13
Q

Why is activation of CD4+ T-cells important for a good therapeutic vaccine?

A

Th-help allows for strongly activated CD8+ T-cells

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14
Q

Which factor do activated CD4+ T-cells express, by which they influence DCs? What are the effects of this? (2)

A

CD40L -> binds to CD40 on DC
1. Release of IL-12 & IFN-γ by DC
2. Expression of CD70 by DC -> binds to CD27 on CD8+ T-cell

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15
Q

What happens in the absence of a CD4+ T-cell response in therapeutic vaccines?

A

Weak and short-lived CD8+ responses

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16
Q

What are factors to consider when choosing an antigen for therapeutic vaccines?

A
  1. Specificity -> antigen only present in tumour tissue
  2. Must be no central tolerance to the antigen
  3. Prevalence in multiple patients -> allows for production of off-the-shelve vaccines
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17
Q

Which types of target antigens can be considerd for therapeutic anti-cancer vaccines? (2) How can they be subdivided (2&3)?

A
  1. Tumour-associated antigens
    -Overexpressed proteins
    -Cancer germline antigens
  2. Tumour-specific antigens
    -Oncoviral antigens
    -Shared neoantigens
    -Private neoantigens
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18
Q

What is the downside of using tumour-associated antigens in therapeutic vaccines?

A

They are not tumour-specific -> also present in healthy tissue

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19
Q

What are the characteristics of overexpressed proteins as antigens for therapeutic vaccines? (3)

A
  1. Variable tumour-specificity
  2. High central tolerance
  3. Often high prevalence in multiple patients
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20
Q

What is an example over overexpressed proteins in tumours?

A

Differentiation antigens

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21
Q

What are cancer testis antigens?

A

Antigens mostly expressed in germline/embryonic tissue, but not in mature tissue

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22
Q

What are the characteristics of cancer testis antigens as antigens for therapeutic vaccines? (3)

A
  1. Re-expression in tumour-tissues -> relatively specific (more so than overexpressed antigens)
  2. Low central tolerance
  3. Often high prevalence in multiple patients
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23
Q

What are oncoviral antigens?

A

Antigens specific to tumour-inducing viruses

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24
Q

What are the characteristics of oncoviral antigens as antigens for therapeutic vaccines? (3)

A
  1. High tumour-specificity
  2. No central tolerance
  3. Often high prevalence in multiple patients
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25
Q

What are examples of oncoviral antigens? (2)

A
  1. HPV proteins in HPV-derived carcinoma
  2. Chronic HBV proteins in HBV-induced HCC
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26
Q

What can be a downside of targeting oncoviral antigens in therapeutic vaccines?

A

Tumours often don’t rely on oncoviral antigens for survival -> can be downregulated

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27
Q

What are shared neoantigens?

A

Neoantigens that are commonly found in multiple patients with a specific type of cancer

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28
Q

What are the characteristics of shared antigens as neoantigens for therapeutic vaccines? (3)

A
  1. High tumour-specificity
  2. No central tolerance
  3. Medium-to-high prevalence in multiple patients
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29
Q

What are private neoantigens?

A

Tumour neoantigens specific to one patient

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30
Q

What are the characteristics of private antigens as antigens for therapeutic vaccines?

A
  1. High tumour-specificity
  2. No central tolerance
  3. Not present in multiple patients
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31
Q

What is the downside of private antigens as a target antigen for therapeutic vaccines?

A

Requires individual vaccine production -> expensive & laborious

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32
Q

By which mechanisms can shared neoantigens be generated? (2)

A
  1. Insertions & deletions causing frameshift across the whole gene
  2. Generation of new HLA-binding motifs by frequently occuring point mutations
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33
Q

How long are peptides in MHCI?

A

~9 amino acids

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34
Q

What happens when peptides >9 amino acids are presented on MHCI? What is the effect of this?

A

Bulging of the peptide -> less immunogenic

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35
Q

What are anchor residues?

A

Dominant positions in the MHCI binding groove that determine which peptides are able to bind. HLA-subtype specific.

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36
Q

Where are the anchor residues of MHCI located?

A

Positions 2 & 9 (mostly)

37
Q

What is the downside of the limited peptide length & anchor residues of MHCI?

A

Not all peptides are able to bind all MHCI -> requires matching of HLA-type to peptide antigens used in therapeutic vaccines

38
Q

Why is MHCII not HLA-restricted? (at least not as badly as MHCI)

A

Less limits on peptide length & less dominant anchor residues

39
Q

What are non-cellular vaccine platforms for therapeutic vaccination? (3)

A
  1. DNA vaccines
  2. RNA vaccines
  3. SLP vaccines
40
Q

What are the advantages of DNA vaccines for therapeutic vaccination? (2)

A
  1. Built-in adjuvants such as CpG, which activates TLR9
  2. Can have built-in co-expression of chemokines to target specific DC subsets
41
Q

What is the disadvantage of DNA vaccines for therapeutic vaccination?

A

Need to be delivered to DCs in vivo -> they need to be the cells presenting the antigens

42
Q

What are the advantages of RNA vaccines for therapeutic vaccination? (2)

A
  1. Built-in adjuvants such as ssRNA & dsRNA
  2. IV lipoplex vaccine can access DCs systemically
43
Q

What is the disadvantage of RNA vaccines for therapeutic vaccination?

A

Need to be delivered to DCs in vivo -> they need to be the cells presenting the antigens

44
Q

What are SLPs?

A

Synthetic long peptides

45
Q

What are the advantages of using SLP vaccines for therapeutic vaccination? (2)

A
  1. Short peptides can be directly presented on MHC
  2. SLPs yield best result with adjuvants and CD4+ T-cell help
46
Q

What is the disadvantage of using SLP vaccines for therapeutic vaccination?

A

No built-in adjuvants

47
Q

What is the advantage of using SLPs over SSPs (synthetic short peptides) for therapeutic vaccination?

A

SSPs can directly bind to MHCI on all cell types -> if presented without inflammatory signals this causes tolerance induction to tumour antigens

SLPs require processing and are therefore most efficiently presented by DCs

48
Q

Why is the use of SLPs more efficient than whole protein antigens for therapeutic vaccination?

A

SLPs only contain the target epitopes -> more concentrated processing & presentation of antigen

49
Q

What is a disadvantage of using SLPs instead of whole protein antigens for therapeutic vaccination?

A

SLPs have limited processing possibilities -> more MHC-restricted

50
Q

Why can short synthetic peptides be used for ex vivo DC loading for therapeutic vaccinations? What is necessary for this to occur?

A

Can directly bind to MHCI on DCs
Condition: the HLA-type of the DC must be compatible with the SSP provided

51
Q

What are the options for ex vivo DC loading for therapeutic vaccination? (5)

A
  1. Synthetic short peptides
  2. SLPs
  3. mRNA/RNA
  4. DNA
  5. Tumour lysate
52
Q

What are disadvantages of ex vivo DC loading? (2)

A
  1. Ex vivo culture leads to decreased capacity to induce a immune response
  2. moDCs can be less functional due to immunosuppressive mechanisms present in cancer patients
53
Q

What are the characteristics of short synthetic peptides (SSP) for therapeutic vaccination? (3)

A
  1. HLA-restricted
  2. No cross-presentation required
  3. Potential for off-target HLA-binding, leading to tolerance induction
54
Q

What are the characteristics of SLPs for therapeutic vaccination? (4)

A
  1. Efficient HLA-I and HLA-II presentation
  2. Less HLA-restricted than SSP
  3. Induces CD4+ and CD8+ T-cells
  4. Only gives linear epitope B-cell responses
55
Q

Why do SLPs only give linear epitope B-cell responses?

A

B-cells recognize tertiaire structures of antigens -> lack of this tertiary structure in SLPs leads to absence of meaningful antibody responses

56
Q

What are the characteristics of whole proteins for therapeutic vaccination? (4)

A
  1. Inefficient cross-presentation
  2. Lower induction of CD8+ due to low cross-presentation
  3. No HLA-restriction
  4. Induces CD4+, CD8+ (weak) & B-cell responses
57
Q

What are the characteristics of cell lysates for DC loading for therapeutic vaccination? (4)

A
  1. Contains multiple antigens
  2. Likely inefficient cross-presentation
  3. No HLA-restriction
  4. Induction of CD4+, CD8+ (weak) and B-cell responses
58
Q

What does HLA restriction of DNA/mRNA therapeutic vaccines depend on?

A

The HLA restriction of the protein encoded by the DNA/mRNA

59
Q

What are the advantages of cellular (DC-based) therapeutic vaccinations? (2)

A
  1. Short peptides can be used without risk of tolerance induction
  2. Well-controlled antigen loading & maturation
60
Q

What are the disadvantages of cellular (DC-based) therapeutic vaccinations? (5)

A
  1. Requires personalized vaccine preparation
  2. Ex vivo culture may impair DC function
  3. Optimal timing & route difficult to establish
  4. Natural DC subsets difficult to purify in large numbers
  5. Variability in quality
61
Q

What are the advantages of non-cellular therapeutic vaccinations? (5)

A
  1. Generic production possible for shared antigens
  2. Stable & easy to manufacture (-> cheap)
  3. Good DC quality
  4. Scarce DC subsets can be cultured in vivo
  5. Optimal timing & route established
62
Q

What is the disadvantage of non-cellular therapeutic vaccinations?

A

Poorly controlled antigen loading and maturation

63
Q

What are the three signals required for effective T-cell priming?

A
  1. Presentation of antigen by MHC to TCR
  2. Costimulatory molecules
  3. Cytokines
64
Q

How can the right cytokine & costimulatory environment for T-cell activation for therapeutic vaccines be achieved?

A

Triggering PRRs on DCs by PAMPs/DAMPs -> use adjuvants

65
Q

What is the result of an absence of a pro-inflammatory cytokine and costimulatory environment on T-cell activation?

A

Tolerance induction to presented antigen

66
Q

What could be a possible application for antigen-loaded DCs that lack inflammatory costimulatory & cytokine signals?

A

Tolerance induction in auto-immune disease

67
Q

What is the advantage & disadvantage of the fact that mRNA/DNA vaccines form their own adjuvant?

A

Advantage: they automatically induce an inflammatory type of DC
Disadvantage: triggering of TLR7 & TLR9 shut down translation -> encoded epitopes less effectively expressed

68
Q

How can non-cellular vaccines be targeted to DCs in vivo, ensuring that antigens are efficiently expressed? (2)

A
  1. Passive targeting: dependent on scavenging & internalization by tissue-resident DCs at injection site
  2. Active targeting: conjugating peptides/proteins/mRNA particles to DC-targeting antibodies/ligands
69
Q

What are antigen vehicles that can be used for active targeting of DCs? (5)

A
  1. Biodegradable nanoparticles
  2. Antigen-antibody conjugates
  3. Antigen-glycan conjugates
  4. Antigen-TLR conjugates
  5. Micro-organism/micro-organism-like particles
70
Q

What are the advantages of active DC targeting? (5)

A
  1. Targeted delivery
  2. Protection of antigen
  3. Biodistribution of antigen
  4. Controlled release of antigen
  5. Allows for specific targeting of DC subsets
71
Q

What are the two methods to assess vaccine-induces immune responses?

A
  1. In vivo: monitoring of cytokines/T-cell activation in patient blood
  2. In vitro experiments to assess T-cell capacity
72
Q

What is the downside of measuring T-cell activation to vaccine antigens in vivo? How can this be resolved?

A

Often low numbers of antigen-specific T-cells -> no reliable data

T-cells can be isolated & expanded in in vitro experiments

73
Q

What is the process of an in vitro experiment to measure T-cell responses to vaccine antigens?

A
  1. PBMCs + moDCs harvested from blood
  2. Cells expsoed to vaccine/vaccine components
  3. Readouts of cytokine production & cellular responses
74
Q

Which in vitro readouts are frequently used to gauge antigen-specific T-cell responses?

A
  1. Supernatant: IFN-γ ELISA (sometimes other cytokines)
  2. ELISPOT IFN-γ to assess cellular function
  3. Flow cytometry to check activation markers
75
Q

What is the advantage of ELISA over ELISPOT? What is the advantage of ELISPOT over ELISA?

A

ELISA = easier to perform, less sensitive
ELISPOT = more difficult to perform, but more sensitive

76
Q

What does enrichment of TCR clonality after antigen exposure in vitro point to?

A

That these T-cells are specific to the antigen used

77
Q

Why is there a need of a therapeutic HBV vaccine?

A

There is currently no curative HBV treatment

78
Q

What is the process required to select good SLPs for a therapeutic vaccine? (3)

A
  1. Immunopeptidomics on antigen-loaded DCs
  2. Immunopeptidomics on diseased hepatocytes
  3. Immunopeptidomics on HBV-expressing cell lines
79
Q

What is an important requirement for SLPs in therapeutic vaccines against chronic viruses?

A

They need to target conserved regions of the virus to not allow the virus to mutate and escape

80
Q

Which strategies can be used to enhance DC therapy anti-cancer efficacy? (2)

A
  1. Targeting the TAM phenotype
  2. Combination with checkpoint blockade
81
Q

What is a TAM?

A

Tumour-associated macrophage

82
Q

What is the most common phenotype of tumour-associated macrophages?

A

M2 phenotype -> immunosuppressive

83
Q

How can TAMs be depleted to allow higher efficacy of DC therapy? What are its effect?

A

CSFR inhibitors -> depletes macrophages
Gives improved anti-tumour effects over DC therapies alone

84
Q

What are immunosuppressive mechanisms of TAMs? (5)

A
  1. Inhibition of DC maturation with IL-10 & TGF-β
  2. Amino acid metabolic starvation of T-cells
  3. Suppression of effector T-cells with prostaglandins
  4. Expression of inhibitory immune checkpoints
  5. Induction of Tregs with IL-10 & TGF-β
85
Q

Which inhibitory immune checkpoints are expressed by TAMs?

A
  1. PD-L1 / PD-L2
  2. B7-H4
  3. VVISTA
86
Q

What is the most commonly used immune checkpoint blockade? How is this achieved?

A

PD-1/PD-L1 blocking -> blocked with antibodies

87
Q

What is the effect of immune checkpoints on the antigen presentation of DCs to T-cells? What effect could blocking these checkpoints have?

A

PD-1/PD-L1 can hamper T-cell priming by DCs in the lymph node -> blocking this enhances T-cell priming by DCs

88
Q

What is the disadvantage of ex vivo loading of DCs when it comes to immune checkpoints?

A

Ex vivo loaded DCs express high(er) PD-L1

89
Q

What are the results of in vivo DC trials for mesothelioma?

A

Response in only a small subset of patients, but can induce durable responses

I&I WC2 (25 decks)

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