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I&I WC2 > Tumor-immunology > Flashcards

Tumor-immunology Flashcards

1
Q

What are the steps of adoptive T cell therapy? (3)

A
  1. Isolation of T cells
  2. Expansion
  3. Transfer back to patients
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2
Q

What are the advantages of T cells in the context of adoptive T cell therapy? (3)

A
  1. Specific
  2. Potent
  3. Long lasting effect
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3
Q

What are the two types of adoptive T cell therapy?

A
  1. Tumor-infiltrating lymphocytes (TIL)
  2. Gene engineered T cell therapy
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4
Q

What is the main reason to use gene-engineered T cell therapy instead of TIL?

A

More specific

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5
Q

What principle underlies gene-engineered T cell therapy?

A

Genetically modified lymphocytes directed against specific targets on tumor cells

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6
Q

How can you make gene-engineered T cell therapy tumor-specific?

A

Use of receptors

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7
Q

Gene engineered T cell therapy: What are the two types of receptors to generate tumor-specific T cells?

A
  1. TCR
  2. CAR
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8
Q

What are the properties of the TCR in the context of gene-engineered T cell therapy? (3)

A
  1. Peptide recognition in MHC
  2. Access to intra-and extracellular peptides
  3. Low-to intermediate binding affinity
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9
Q

What are the properties of the CAR in the context of gene-engineered T cell therapy? (3)

A
  1. Peptide recognition independent from MHC
  2. Access to extracellular peptides
  3. High binding affinity
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10
Q

Main challenges of T cell therapy (2)

A
  1. Expand number of targets
  2. Increase longevity of T cells
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11
Q

What are the requirements for good targets for adoptive T cell therapy? (5)

A
  1. Not in healthy tissue
  2. Multiple tumor types
  3. Shared among patients
  4. Immunogenic
  5. Related to oncogenesis
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12
Q

Which antigens are typical targets for TCR T cell therapy? (5)

A
  1. Oncoviral antigens
  2. Neoantigens
  3. Differentiation antigens
  4. Over-expressed antigens
  5. Cancer germline antigens
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13
Q

Name examples of oncoviral antigens (2)

A
  1. EBV
  2. HPV
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14
Q

What is an example of a differentiation antigen?

A

Gp100

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15
Q

Name examples of cancer germline antigens (4)

A
  1. NY-ESO1
  2. Testis
  3. Ovary
  4. Placenta
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16
Q

Adoptive T cell therapy: When selecting your epitopes, which parameters do you need to consider specifically? (2)

A
  1. Cross-reactivity
  2. HLA-A2 avidity (high in The Netherlands)
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17
Q

What is your TCR construct based on?

A

Identification of TCR genes using an optimized T cell:DC co-culture -> to see which TCR in human blood are present that bind this epitope

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18
Q

What are the steps of the optimized T cell:DC co-culture? (3)

A
  1. Co-culture
  2. Epitope-specific T cells
  3. Sort T cell and identify TCR genes
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19
Q

Adoptive T cell therapy: What happens after identification of TCR genes?

A

Enrichment of epitope-specific TCRs

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20
Q

What is meant with ‘sensitivity’ in adoptive T cell therapy?

A

TCRs recognize endogenously presented epitopes

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21
Q

What is meant with ‘specificity’ in adoptive T cell therapy?

A

Only recognition of cells expressing our antigen and not other cell lines

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22
Q

What is meant with ‘sensitivity’ in adoptive T cell therapy?

A

Proved to prove patient-derived tumeroids and xenografts

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23
Q

Adoptive T cell therapy: why do you use epigenetic pre-conditioning of T cells?

A

To enhance tumor cell antigen presentation

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24
Q

What is the main outcome in clinical trials when studying TCR T cell treatment?

A

Tumors initially regress but in most cases relapse again

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25
Q

How can we increase the longevity of T cells by outsmarting the tumor and its evasive mechanisms? (4)

A
  1. Co-stimulatory TCRs/CARs
  2. Chemokine/cytokine receptors
  3. Inducible mediators
  4. Gene depletion/silencing
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26
Q

How can a TCR with built in co-stimulation look like? (3)

A
  1. Extracellular domain for antigen binding
  2. Transmembrane structure (CD28 necessary)
  3. Intracellular (variable)
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27
Q

What are the steps of the cancer immunotherapy cycle? (7)

A
  1. Release of cancer cell antigens
  2. Cancer antigen presentation
  3. Priming and activation
  4. Trafficking of T cells to tumors
  5. Infiltration of T cells into tumors
  6. Recognition of cancer cells by T cells
  7. Killing of cancer cells
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28
Q

What is the central role for DCs in the initiation/tuning of adaptive immunity? (3)

A
  1. Present internalized antigens on MHCII and MHCI
  2. Migration to LN
  3. Activation/skewing of naïve T cell responses
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29
Q

What are ways for tumor cells to be destroyed? (2)

A
  1. Lack of nutrients or oxygen in the tumor core
  2. Therapy
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30
Q

What are tumor antigens?

A

Antigens that are different than those of healthy cells

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31
Q
A

Tumor antigen presented by DC -> T cell activation -> travel via lymphatics back to the tumor -> tumor destroyed

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32
Q

Why do we need a therapeutic vaccination to combat viral infection?

A

This mounts a cellular immune response -> prophylactic vaccinations only mount an humoral immune response

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33
Q

What is cross-presentation?

A

Presentation of endocytosed antigens on MHC-I

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34
Q

How are antigens presented on MHC-I?

A

Cytosolic antigens -> proteasomal route -> Loaded on MHC-I in ER

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35
Q

How are antigens presented on MHC-II? (3)

A
  1. Endocytosis
  2. Degradation by local proteases
  3. Loaded on MHC-II
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36
Q

How do endocytosed antigens end up in the MHC-I complex? (2)

A
  1. Cytosolic diversion of endocytosed antigens
  2. Exchange of peptides in the endosome
37
Q

What encompasses the process of cytosolic diversion of endocytosed antigens leading to MHC-I presentation? (3)

A
  1. Endocytosis
  2. Cytosolic diversion of endocytosed antigen
  3. Proteasomal degradation route
38
Q

Which property of dendritic cells is exploitated in therapeutic vaccination?

A

It’s ability to cross-present very well

39
Q

How do therapeutic vaccines drive both the CD4- and CD8 T cell response?

A

Vaccines can enter the DCs

40
Q

CD4+ T cells, after recognizing its antigen on DCs, give a feedback signal. What are the steps of this feedback signal? (4)

A
  1. CD40L (T cell) binds to CD40 (DC)
  2. DC secretes cytokine (IL-12, INFy)
  3. Upregulation of CD70
  4. CD70 binds to CD27 on CD8+ T cells
41
Q

Super-activation of CD8+ T cells causes? (2)

A
  1. Potent effector signal
  2. Long-lived
42
Q

Which two steps of the feedback signal provided by DCs/CD4+ T cells super activate CD8+ T cells?

A
  1. Secretion of cytokines by DC
  2. CD70-CD27 signal
43
Q

True or false: CD8+ T cells that have not been super activated by the feedback signal provided by CD4+ T cells travel less well

44
Q

True or false: Activated CD8+ T cells which receive help signals can migrate, proliferate and recognize it’s target at the tumor

45
Q

True or false: prophylaxis is more aimed at T cells

A

False -> more aimed at B cells

46
Q

What are the requirements for successful therapeutic vaccination? (2)

A
  1. Reach DCs
  2. DC and disease target cell present exact same peptide on MHCI
47
Q

Which two types of target antigens exist?

A
  1. Tumor-associated antigens
  2. Tumor-specific antigens
48
Q

Which two types of tumor-associated antigens exist?

A
  1. Overexpressed proteins, differentiation antigens
  2. Cancer testis antigens
49
Q

What are the characteristics of over expressed proteins/differentiation antigens? (3)

A
  1. Variable tumor specificity
  2. High central tolerance
  3. High prevalence in multiple patients
50
Q

What are the characteristics of cancer testis antigens? (3)

A
  1. Good tumor specificity
  2. Low central tolerance
  3. High prevalence in multiple patients
51
Q

Which three types of tumor-specific antigens exist?

A
  1. Onco-viral antigens
  2. Shared neoantigens
  3. Private neoantigens
52
Q

What are the characteristics of onco-viral antigens? (3)

A
  1. Ideal tumor specificity
  2. No central tolerance
  3. High prevalence in multiple patients
53
Q

What are the characteristics of shared neoantigens? (3)

A
  1. Ideal tumor specificity
  2. No central tolerance
  3. High prevalence in multiple patients
54
Q

What are the characteristics of private neoantigens? (3)

A
  1. Ideal tumor specificity
  2. No central tolerance
  3. Low prevalence in multiple patients
55
Q

How do neoantigens arise?

56
Q

Mutations can give rise to neoanitigen if either… is affected? (3)

A
  1. Peptide generation (protein cleavage)
  2. MHC binding
  3. TCR recognition
57
Q

Neoepitopes: What is an example of a non-immunogenic point mutation?

A

Mutant aa faces away from TCR

58
Q

Neoepitopes: What are examples of immunogenic point mutations? (2)

A
  1. Mutant anchor residue
  2. Mutant aa projects towards TCR
59
Q

What is the main mutation that leads to a source of shared neo-epitopes?

A

Frame shift

60
Q

What are the three non-cellular vaccine platforms?

A
  1. DNA vaccine
  2. RNA vaccine
  3. Peptide vaccine
61
Q

What are the specific adjuvants added to DNA/RNA vaccinations?

A
  1. DNA -> built in adjuvant TLR ligand to recognize as foreign
  2. RNA -> built in adjuvant such as ssRNA and dsRNA
62
Q

True or false: peptide vaccines have no built in adjuvant

63
Q

What is the main cellular vaccine platform?

A

DC-based vaccination

64
Q

What are the steps of loading DCs with antigen to generate a DC-based vaccine? (5)

A
  1. Take DC out person
  2. Differentiate
  3. Ex vivo culture
  4. Load DC ex vivo with antigen
  5. Return antigen loaded DC
65
Q

How do you mature DCs ex vivo?

A

Provide antigen

66
Q

Why are primary DCs preferred over monocyte-derived DC?

A

Monocyte-derived DC can be subject to tumor immune suppression

67
Q

What are the antigen forms for vaccination (DC-based and non-cellular)? (5)

A
  1. Short peptides
  2. Long peptides
  3. Proteins
  4. Cell lysates
  5. mRNA/DNA
68
Q

What are the characteristics of short peptides as antigen form for vaccination? (3)

A
  1. HLA restricted (Mostly HLA-I)
  2. No X-presentation required
  3. Non cellular: off-target HLA binding + tolerance
  4. 9-11 aa
69
Q

What are the characteristics of long peptides as antigen form for vaccination? (5)

A
  1. Efficient HLA I and II
  2. Less HLA restriction
  3. CD4/8 responses
  4. Only linear epitope B cell responses
  5. 25-40aa
70
Q

What are the characteristics of proteins as antigen form for vaccination? (3)

A
  1. Inefficient cross presentation
  2. No HLA restriction
  3. CD4/8 and B cell responses
71
Q

Why is there inefficient cross presentation when using proteins as antigen form for vaccination? (2)

A
  1. Less concentrated epitope
  2. Processing needed -> destruction of epitope
72
Q

What are the characteristics of cell lysates as antigen form for vaccination? (4)

A
  1. Multiple antigens
  2. Inefficient cross presentation
  3. No HLA restriction
  4. CD4/8 and B cell responses
73
Q

What are the characteristics of mRNA/DNA as antigen form for vaccination? (5)

A
  1. Coding for protein/peptide/long peptide
  2. Antigen presentation efficiency unclear
  3. HLA restriction depends on code
  4. CD4/8 and B cell responses
  5. Instable
74
Q

Pick: Short/long peptides can be used without risk

A

Short peptides

75
Q

Why are cellular DC-based vaccines costly and time consuming?

A

Required personalized vaccine preparation

76
Q

What are difficulties arising with cellular DC-based vaccination? (4)

A
  1. Ex vivo culture may impair DC function
  2. Optimal timing and route difficult
  3. Natural DC subsets difficult to purify in large numbers
  4. Variability in quality
77
Q

What is needed for effective T cell priming? (3)

A
  1. Signal 1 -> TCR/CD28
  2. Signal 2 -> CD40/CD40L
  3. Signal 3 -> CD80/CTLA4
78
Q

How do you obtain an appropriate immunological response using DCs?

A

Target/use the right (combination) of DC subset(s) with the right PAMP/DAMP

79
Q

Why is it important to target/use the right (combination) of DC subset(s) with the right PAMP/DAMP to obtain an appropriate immune response?

A

DC subsets respond to different PAMPs/DAMPs and have different functions

80
Q

How do you achieve targeting/using the right (combination) of DC subset(s) with the right PAMP/DAMP? (2)

A
  1. Platform type (RNA/DNA)
  2. Added adjuvant
81
Q

True or false: in vivo targeting of non-cellular vaccines does not rely on DCs for effect

82
Q

Which two types of in vivo targeting of non-cellular vaccines exist?

A
  1. Passive targeting
  2. Active targeting
83
Q

What does passive targeting entail?

A

Protein/SLP vaccines require DCs for processing/effect

84
Q

What does active targeting entail?

A

Proteins/peptides/mRNA particles conjugated to antibodies/ligands for specific DC-surface markers

85
Q

What are important factors to consider about an antigen vehicle? (4)

A
  1. Targeted delivery
  2. Protection
  3. Biodistribution
  4. Controlled release
86
Q

What are examples of antigen vehicles? (5)

A
  1. Biodegradable nanoparticles
  2. Antigen-antibody conjugates
  3. Antigen-glycan conjugates
  4. Antigen-TLR conjugates
  5. Microorganism
87
Q

Nanoparticles: Why does size matter?

A

Depends on if you have to cross the endothelium -> makes a difference in which cell types are reached

88
Q

What would be the future for DC-based vaccination?

A

Replacing DCs by artificial APCs

I&I WC2 (22 decks)

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