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Immunology: Research + Clinic > HC4: Tumor immunology, cellular therapy and TLR agonists > Flashcards

HC4: Tumor immunology, cellular therapy and TLR agonists Flashcards

HC4

1
Q

True or False: Immunocompromised individuals are more likely to develop cancer

A

True
> Eldery
> AIDS in HIV patients: low CD4+ T-cells
> immunosuppressive therapy

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2
Q

Which cells are present in draining lymph nodes of tumor

A

Tumor infiltrating lymphocytes (TILs) > point towards immune activation by tumors

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3
Q

Tumor cells are controlled by immune surveillance. What is immune surveillance?

A

A number of immune cells that can recognize and eliminate tumor / premalignant cells (elimination phase)
> need for antigenic difference between tumor cell and normal cell: this difference is recognized (sugars, proteins etc)
> eliminate mutated cells

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4
Q

Immune surveillance on daily basis

A

Happens a lot
> many mutated cells removed on regular basis
> many cells involved: CD4 and CD8+ T-cells, CD8+ CTLs, NK cells, etc

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5
Q

What is presented on premalignant cells for immune surveillance? Which cells react? And how?

A

Strange mutated peptide on MHC-I > recognized as foreign
> recognized by CTLs to kill: perforins and granzymes to induce apoptosis
> NK cells involved, if tumor cells develop immune escape and do not present on MHC-I by downregulation: NK cells recognize those cells with NK receptor ligands but no MHC-I > apoptosis induced like CTL
> Complement: via antibodies: classical route
> Antibodies

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6
Q

Immune cells and tumor cell death

A

Cell mediated: CTL, NK cell
Antibody mediated:
> Opsonization/lysis: complement factors bind to antibodies and complement recognized by macrophages and neutrophils etc: killing
> ADCC: macrophages recognize cell when antibody bound: macrophages and Nk cells have Fc receptors > antibody depedent cellular cytotoxicity (ADCC): killing

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7
Q

Immune surveillance maintains the elimination phase of premalignant cells. When is a equilibrium phase reached?

A

If variant tumor cells arise that are more resistant to being killed > over time variety of different tumor variants develop
» equilibrium

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8
Q

Escape phase tumor cells

A

One variant is not recognized over time > escape killing or recruit regulatory cells to protect it > unchallenged spread

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9
Q

Escape of tumor cells of immune surveillance is based on which characteristics:

A
  • Genetic instability of tumor cells
  • Continuous immunological pressure
    » selection of non-immunogenic variants
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10
Q

Escape phase is induced by a combination of:

A
  • Immune escape mechanism
  • Limited potential to kill cells
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11
Q

Shortcomings in immune reaction against tumors: immune system

A
  • Clonal deletion causes low number of specific T-cells which have low/intermediate TCR affinity
    > negative selection: because self-reactive
    > some do go through, but low affinity for self-peptides
  • Inefficient stimulation and boost because of low activation of innate immune cells (APCs) by the tumor
    > no danger like pathogen
    > no costimulation
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12
Q

Shortcomings in immune reaction against tumors: Tumor part

A

Immune escape
- Low immunogenicity
> Lower expression MHC-I: a bit, so hat NK cells do not kill
> No adhesion molecules
> No co-stimulatory molecules

  • Tumor treated as self antigen, after uptake antigen by APC, no TLR activation so no costimulation induced for T-cell, tolerant T-cells induced
  • Antigenic modulation: Tumor antigen deficient variants: no protein expression (of antigen): not recognized
  • Upregulation of anti-apoptotic molecules: to downregulate granzymes
  • Tumor-induced immune suppression: secretion suppressive molecules: IL-10, TGFb, VEGF
    > IDO breaks down important amino acids for T-cells
    > attracting suppressive immune cells: Tregs, iDCs, MDSCs
    > expression PD-L1
  • Tumor-induced privileged site: factors secreted that create physical barrier for immune cells
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13
Q

3 stumbling blcoks in tumor-specific T-cells

A

1: low T-cell numbers and low TCR affinity
2: Inefficient priming and boosting of tumor
3: T-cell suppression in tumor microenvironment: Ag persistence.

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14
Q

Variety in prevalence somatic mutations in various human cancers

A

Some have more mutations > more neo-antigens made, better recognized by immune system
> not every tumor is the same
> immune therapies more successful if more somatic mutations > discovery new neo-antigens for therapy

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15
Q

Immunotherapy for cancer concept

A

Shortcomings in normal immune system against tumor cells > strengthen immune response

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16
Q

Passive vs active tumor immunotherapy

A
  • Passive: no stimulation of own adaptive immune system
  • Active: stimulation of own adaptive immune system
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17
Q

Passive immunotherapy types

A

1 Interleukines and cytokines
2 Tumor-specific antibodies
3 Adoptive T-cell therapy (ATC)

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18
Q

Interleukine and cytokine immunotherapy

A

Aspecific and very toxic
> like IL-2

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19
Q

Tumor-specific antibodies

A

Are coupled to cytotoxic drugs, toxins or radio-isotopes

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20
Q

Requirements tumor-specific antibody

A
  • Antibodies need to recognize an antigen which is not or lowly expressed in other tissues
  • Antigen needs to be present on cell surface (threedimensional)
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21
Q

How do tumor-specific antibodies, Ab fragments conjugated to toxin and rafionuclide work

A

Ab: bind tumor cell, NK cells with Fc receptors (CD16) are activated to kill tumor cells
Toxin-conjugate: conjugate binds cell > internalized > killing
Radionuclide-conjugate: binds cell > radiation kills tumor cell and neighboring tumor cells

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22
Q

Bi-specific antibodies for tumor (bsAbs)

A

Bind tumor antigen and T-cell to activate the T-cell
> one Fab binds antigen
> one Fab binds T-cell
» bring in proximity

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23
Q

BiTEs

A

Small fragments, bind variable elements of each other of T-cell and tumor antigen > improve recognition of tumor antigens

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24
Q

Challenges for bsAbs

A
  • Toxicity (related to the expression of tumor antigen): damage to own tissues, expression antigen on healthy cells
  • Low tissue penetration (especially IgG based bsAbs)
  • Low serum half-life of smaller bsAbs (BiTEs and dAbs) > BiTEs are smaller though and can penetrate better
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25
Conclusions tumor-specific antibodies
- Limited effect on solid tumors - Tumor antigen needs to be present on cell membrane
26
Adoptive T-cell therapy (ATC): TILs
Tumor infiltrating lymphocytes (patients own cells used) > Tumor isolation > fragmentation of tumor mass > T-cell growth factors added > Activation and selection of T-cells > Expansion tumor-specific T-cell populations ex vivo > Infusion in irradiated patient with chemotherapy
27
Assumption TIL therapy
The T-cells in the tumor are directed to the tumor
28
Mechanism TIL therapy
Irradiation/chemo > decreased immunosuppression by Tregs and MDSCs and dying tumor cells > administered TILs > antigen presentation increased and T-cell expansion ans killing
29
Why irradiation in TIL therapy
Decrease immunosuppression when administering TILs > some active immune reaction, less immune suppressive environment > more own immune cells active
30
ATC: Retroviral transduction of tumor-specific TCR in lymphocytes
T-cells which are successful in patient A are isolated > take TCR > clone TCR and transduce T-cells of patient B with virus > if for example good recognition of prostate cancer antigens. > neo-antigen specific TCRs
31
Matching in retroviral TCR transfer ATC
If TCR cloned > HLA matching > same MHC must be recognized (other HLA types, other MHC-I)
32
Problem TCR transfer ATC
T-cells switch their alpha and beta chains: donor TCR and recipient own TCR both expressed and recombination > other TCR with other specificity, causing auto-reactivity >> solved: now only reaction with own a and b chains
33
ATC: CAR T-cell therapy
Chimeric Antigen Receptor > CAR construct put in T-cells >> Ligand binding domain (extracellular) and signalling domain (intracellular) > variable domain BCR with TCR signalling domains > signalling domains for CD28 (costimulation, strengthen response) and TCR signalling
34
Antigen recognized by CAR
Threedimensional and surface expressed > for BCR >> for TCR: can be cytoplasmic protein expressed on MHC-I, for BCR, no
35
Matching for CAR T-cells
No HLA matching restriction like in TCR transfer > three dimensional epitope, no MHC involved
36
Tumor escape variants of CAR T-cells and auto-reactivity problem
- Downregulation surface expressed antigen - Possibly auto-reactivity against own cells for example B-cell lymphoma, immunocompromised > need antibody donations ( if for CD19 epitope) - Strategy: only focus on lambda or kappa light chain of CD19 to prevent autoreactivity against all B-cells
37
Difference signalling TCR and CAR
No immunological synapse with cSMAC and pSMAC in CAR: good organization of signals: more proliferation and signalling: all through receptor ligand interactions. > actin adhesion is formed, but no cSMAC > costimulatory signals in intracellular domain, other clustering, other activation of T-cell: ability to kill but less expansion > microclusters > bigger clusters of signals (interactions) needed for optimal expansion: different signalling
38
Difference of signalling effect for TCR transduction vs CAR T-cells
T-cells of TCR transduction can survive longer in patients than CAR T-cells > more expansion because bigger cluster of signals
39
Both TCR transfer and CAR-T-cells have similar procedure
Harvest T-cells > genetically engineer cells > either TCR or CAR > T-cell activation and infuse back
40
Passive immunotherapy: protein and T-cells
Protein > cytokines > antibodies T-cells: ATC > TILs > TCR transduction > CAR T-cells
41
Active immune therapy
- Blockade of immunological checkpoints on T-cells - Vaccination approaches. - Dendritic cells (DCs): loaded with tumor (neo-) antigens
42
Immune checkpoint inhibition concept
Block immunological checkpoints as therapy > block co-stimulatory CTLA4 and PD1
43
CTLA4 block why
> to let naive T-cell react to APC: costimulation CD28 to CD80/86 needed > CTLA4 competes of the Treg > CTLA4 wins of CD28 for the CD80/86 > immune response dampened to regulate it > In tumor response, already low T-cells > block CTLA4: more T-cells matured and expand in LN to attack tumor
44
PD-1 block
PD-1 of active T-cell can bind PD-L1 of tumor cell > exhausted T-cells created > granules work less well: exhaustion >> normally, an APC can upregulate PD-L1 to regulate activated T-cell >> in LN: only TCR response and no CD28 costimulation: anergy >> cancer cell does negative regulation of T-cell in periphery with PD-L1
45
Block CTLA4 and PD-1 and PD-L1: which phases
CTLA4: priming phase PD-1/PD-L1: effector phase
46
names anti PD1 and anti CTLA4
Nivolumab (PD1) and Ipilimumab (CTLA4)
47
TILs vs ipilimumab in advanced melanoma
TILs work better > in insurance
48
Problem ICI (immune checkpoint inhibition)
Overactive immune system induced > auto-immune symptoms > too heavy response
49
Vaccination approaches immunotherapy
- Selected tumor antigens (peptides) > tumor stimulates innate cells not well, not effective - Whole tumor cells - Whole tumor cells in presence of adjuvant (eg BCG) - Neo-antigens >like Frame therapeutics: Curevac > vaccination strategy based on neo-antigens caused by frameshifts
50
DC immunotherapy concept
Loaded with (neo)antigens > patients make T-cells themselves > memory made (not with CARs for example)
51
Why DCs used and not macrophages in immunotherapy
- Can activate naive T-cells - Can cross-present antigens - Good co-stimulation
52
Importance co-stimulation for immunotherapy
Otherwise: activation induced cell death by TCR signal only of T-cell or T-cell anergy
53
Cross-presentation by DCs
Present on MHC-I and MHC-II > tumor phagocytosis > MHC-II path for CD4 T-cell > also peptides to ER to load MHC-I on ER and via Golgi present on membrane for CD8 T-cell
54
DC immunotherapy successes or not
- Treatment very severe patients - Antigen loading of DC is not optimal - DC maturation (activation) - Route of application - Immune suppressive environment of tumor
55
DC therapy process
- Monocytes isolated from blood (too little DCs in blood) - Add GM-CSF and IL-4 for differentiation - iDCs need to be activated to mature to mDC and upregulation of co-stimulatory molecules (CD80/86) and present right antigens (maturation mix added) - Th1 response wanted (support CTLs maturation) > IL-12 production wanted - Antigen loading of mDCs if they make IL-12 and can migrate - Administer to patients
56
Requirements DC for therapy
- Presentation antigen on MHC - Co-stimulation - Cytokines for Th1 polarization: IL-12 - Migration capacity towards LNs - induce CTL response
57
The production of IL-12 and upregulation costimulatory molecules by DCs is normally determined by?
TLR signal
58
DC maturation cocktail: MPLA: monophosphoryl lipid A
MPLA: non toxic variant of LPS > activate TLR4
59
Problem gold standard maturation mix for DCs (IL-1b, TNFa, PGE2)
No IL-12 made
60
LPS not used in maturation mix?
Very toxic in patients
61
MPLA + IFN-y
Optimal for DCs for immunotherapy > Costimulation > MHC-II Ag presentation > migration, less than gold standard, but good enough > IL-12
62
What does chemokine receptor presence say about migration capacity of DCs?
It does not imply the signalling through this receptor > migration assay like Transwell
63
Cytokine production test
ELISA
64
Less IL-10 produced by DCs for immunotherapy is ...
Good, less anti-inflammatory cytokines
65
How to check if DCs give Th1 response
Flow cytometry after co-culture > IFN-y gating for Th1 and IL-4 for unwanted Th2
66
How to test effect DC therapy on CTLs
Find antigen specific CTLs > recognize MHC-I with peptide on an APC > recreate MHC-I on fluorophore > HLA-peptide tetramers / MHCI tetramers > flow cytometry > with MPLA + IFN-y mix more MHCI interaction+ CTLs when incubated with DCs > more specific CTLs
67
Multiple doses of MoDCs therapy in clinic, why?
Expansion is induced repeatedly
68
in vivo targeting of DCs, why?
- Cheaper - Less control on DC modulation > controls to check if activation is good etc > you do not want anergic T-cells by missing of co-stimulation - Not ex vivo differentiation and maturation - less complex - On DC > specific proteins for DCs > targeted > antigens and adjuvants to cells directly for presentation
69
How to induce T-cell and B-cell responses actively?
- Injection DCs - Targeting DCs - Indirect targeting DCs by vaccination - ICI: influence T-cell differentiation
70
Why immunotherapy in combination with chemo or radiation and surgery
Because large tumor is very immune suppressive > combination > less Tregs > mainly for metastases as well
71
Future cancer immunotherapy
Personalized medicine with neo-antigens Combine immune activation and disruption immune suppression
72
Side effects cancer immunotherapy
- Auto-reactivity like vitiligo in melanoma - Reaction against own antigens because similarity to tumor antigens > often: the more successful the immunotherapy, the bigger the side effects

Immunology: Research + Clinic (7 decks)

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