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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
How can we increase the longevity of T cells by outsmarting the tumor and its evasive mechanisms? (4)
1. Co-stimulatory TCRs/CARs 2. Chemokine/cytokine receptors 3. Inducible mediators 4. Gene depletion/silencing
26
How can a TCR with built in co-stimulation look like? (3)
1. Extracellular domain for antigen binding 2. Transmembrane structure (CD28 necessary) 3. Intracellular (variable)
27
What are the steps of the cancer immunotherapy cycle? (7)
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
28
What is the central role for DCs in the initiation/tuning of adaptive immunity? (3)
1. Present internalized antigens on MHCII and MHCI 2. Migration to LN 3. Activation/skewing of naïve T cell responses
29
What are ways for tumor cells to be destroyed? (2)
1. Lack of nutrients or oxygen in the tumor core 2. Therapy
30
What are tumor antigens?
Antigens that are different than those of healthy cells
31
Tumor antigen presented by DC -> T cell activation -> travel via lymphatics back to the tumor -> tumor destroyed
32
Why do we need a therapeutic vaccination to combat viral infection?
This mounts a cellular immune response -> prophylactic vaccinations only mount an humoral immune response
33
What is cross-presentation?
Presentation of endocytosed antigens on MHC-I
34
How are antigens presented on MHC-I?
Cytosolic antigens -> proteasomal route -> Loaded on MHC-I in ER
35
How are antigens presented on MHC-II? (3)
1. Endocytosis 2. Degradation by local proteases 3. Loaded on MHC-II
36
How do endocytosed antigens end up in the MHC-I complex? (2)
1. Cytosolic diversion of endocytosed antigens 2. Exchange of peptides in the endosome
37
What encompasses the process of cytosolic diversion of endocytosed antigens leading to MHC-I presentation? (3)
1. Endocytosis 2. Cytosolic diversion of endocytosed antigen 3. Proteasomal degradation route
38
Which property of dendritic cells is exploitated in therapeutic vaccination?
It's ability to cross-present very well
39
How do therapeutic vaccines drive both the CD4- and CD8 T cell response?
Vaccines can enter the DCs
40
CD4+ T cells, after recognizing its antigen on DCs, give a feedback signal. What are the steps of this feedback signal? (4)
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
Super-activation of CD8+ T cells causes? (2)
1. Potent effector signal 2. Long-lived
42
Which two steps of the feedback signal provided by DCs/CD4+ T cells super activate CD8+ T cells?
1. Secretion of cytokines by DC 2. CD70-CD27 signal
43
True or false: CD8+ T cells that have not been super activated by the feedback signal provided by CD4+ T cells travel less well
True
44
True or false: Activated CD8+ T cells which receive help signals can migrate, proliferate and recognize it's target at the tumor
True
45
True or false: prophylaxis is more aimed at T cells
False -> more aimed at B cells
46
What are the requirements for successful therapeutic vaccination? (2)
1. Reach DCs 2. DC and disease target cell present exact same peptide on MHCI
47
Which two types of target antigens exist?
1. Tumor-associated antigens 2. Tumor-specific antigens
48
Which two types of tumor-associated antigens exist?
1. Overexpressed proteins, differentiation antigens 2. Cancer testis antigens
49
What are the characteristics of over expressed proteins/differentiation antigens? (3)
1. Variable tumor specificity 2. High central tolerance 3. High prevalence in multiple patients
50
What are the characteristics of cancer testis antigens? (3)
1. Good tumor specificity 2. Low central tolerance 3. High prevalence in multiple patients
51
Which three types of tumor-specific antigens exist?
1. Onco-viral antigens 2. Shared neoantigens 3. Private neoantigens
52
What are the characteristics of onco-viral antigens? (3)
1. Ideal tumor specificity 2. No central tolerance 3. High prevalence in multiple patients
53
What are the characteristics of shared neoantigens? (3)
1. Ideal tumor specificity 2. No central tolerance 3. High prevalence in multiple patients
54
What are the characteristics of private neoantigens? (3)
1. Ideal tumor specificity 2. No central tolerance 3. Low prevalence in multiple patients
55
How do neoantigens arise?
Mutations
56
Mutations can give rise to neoanitigen if either... is affected? (3)
1. Peptide generation (protein cleavage) 2. MHC binding 3. TCR recognition
57
Neoepitopes: What is an example of a non-immunogenic point mutation?
Mutant aa faces away from TCR
58
Neoepitopes: What are examples of immunogenic point mutations? (2)
1. Mutant anchor residue 2. Mutant aa projects towards TCR
59
What is the main mutation that leads to a source of shared neo-epitopes?
Frame shift
60
What are the three non-cellular vaccine platforms?
1. DNA vaccine 2. RNA vaccine 3. Peptide vaccine
61
What are the specific adjuvants added to DNA/RNA vaccinations?
1. DNA -> built in adjuvant TLR ligand to recognize as foreign 2. RNA -> built in adjuvant such as ssRNA and dsRNA
62
True or false: peptide vaccines have no built in adjuvant
True
63
What is the main cellular vaccine platform?
DC-based vaccination
64
What are the steps of loading DCs with antigen to generate a DC-based vaccine? (5)
1. Take DC out person 2. Differentiate 3. Ex vivo culture 4. Load DC ex vivo with antigen 5. Return antigen loaded DC
65
How do you mature DCs ex vivo?
Provide antigen
66
Why are primary DCs preferred over monocyte-derived DC?
Monocyte-derived DC can be subject to tumor immune suppression
67
What are the antigen forms for vaccination (DC-based and non-cellular)? (5)
1. Short peptides 2. Long peptides 3. Proteins 4. Cell lysates 5. mRNA/DNA
68
What are the characteristics of short peptides as antigen form for vaccination? (3)
1. HLA restricted (Mostly HLA-I) 2. No X-presentation required 3. Non cellular: off-target HLA binding + tolerance 4. 9-11 aa
69
What are the characteristics of long peptides as antigen form for vaccination? (5)
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
What are the characteristics of proteins as antigen form for vaccination? (3)
1. Inefficient cross presentation 2. No HLA restriction 3. CD4/8 and B cell responses
71
Why is there inefficient cross presentation when using proteins as antigen form for vaccination? (2)
1. Less concentrated epitope 2. Processing needed -> destruction of epitope
72
What are the characteristics of cell lysates as antigen form for vaccination? (4)
1. Multiple antigens 2. Inefficient cross presentation 3. No HLA restriction 4. CD4/8 and B cell responses
73
What are the characteristics of mRNA/DNA as antigen form for vaccination? (5)
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
Pick: Short/long peptides can be used without risk
Short peptides
75
Why are cellular DC-based vaccines costly and time consuming?
Required personalized vaccine preparation
76
What are difficulties arising with cellular DC-based vaccination? (4)
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
What is needed for effective T cell priming? (3)
1. Signal 1 -> TCR/CD28 2. Signal 2 -> CD40/CD40L 3. Signal 3 -> CD80/CTLA4
78
How do you obtain an appropriate immunological response using DCs?
Target/use the right (combination) of DC subset(s) with the right PAMP/DAMP
79
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?
DC subsets respond to different PAMPs/DAMPs and have different functions
80
How do you achieve targeting/using the right (combination) of DC subset(s) with the right PAMP/DAMP? (2)
1. Platform type (RNA/DNA) 2. Added adjuvant
81
True or false: in vivo targeting of non-cellular vaccines does not rely on DCs for effect
False
82
Which two types of in vivo targeting of non-cellular vaccines exist?
1. Passive targeting 2. Active targeting
83
What does passive targeting entail?
Protein/SLP vaccines require DCs for processing/effect
84
What does active targeting entail?
Proteins/peptides/mRNA particles conjugated to antibodies/ligands for specific DC-surface markers
85
What are important factors to consider about an antigen vehicle? (4)
1. Targeted delivery 2. Protection 3. Biodistribution 4. Controlled release
86
What are examples of antigen vehicles? (5)
1. Biodegradable nanoparticles 2. Antigen-antibody conjugates 3. Antigen-glycan conjugates 4. Antigen-TLR conjugates 5. Microorganism
87
Nanoparticles: Why does size matter?
Depends on if you have to cross the endothelium -> makes a difference in which cell types are reached
88
What would be the future for DC-based vaccination?
Replacing DCs by artificial APCs

I&I WC2 (16 decks)

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