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Oncology lecture B > Mres cohort lectures > Flashcards

Mres cohort lectures Flashcards

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1
Q

What is a TCR modified T cell?

A

Autologous T cell expansion of TILS with a modified T cell for the cancer

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2
Q

What is a CAR T cell?

A

Autologous t cells which have an artificial immune receptor

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3
Q

How do tumour cell drive immune tolerance?

A 
Down reg MHC
Up reg FAS ligand 
Down reg co-stimulatory (CD80)
produce immuo-supressive factors ( TGF-b, IL-6)
immunosuppressive cells
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4
Q

What immunotherapy suppressive cells are there?

A

Treg
MDSC (myeloid derived sup. cells)
Tumour associated macrophages

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5
Q

How are TILS used?

A

Tumor infiltrating lymphoctyes are directly injected into tumour.

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6
Q

Challenges against TILS?

A
  • work in hot tumours
  • difficult to harvest from excised tumour
  • inhibited by TME
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7
Q

Do CAR need MHC?

A

No

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8
Q

Does CAR need signals 1 and 2 for activation?

A

NO

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9
Q

How does CAR kill tumours

A

cytotoxic action

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10
Q

CAR-T cells toxicity syndromes?

A

Tumour lysis syndrome

Cytokine storm

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11
Q

Sx of cytokine storm?

A

hypotension

fever

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12
Q

Sx of tumour lysis syndrome?

A

metabolic complications.

  • abdo pain, distension,
  • Urinary (think rhabdomyolysis)
  • Hypocalcaemia (thrones, grows etc.)
  • Hyperkalaemia (weekness and paralysis)
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13
Q

What is an off target toxicity?

A

CAR directed at same epitope but not at tumour (HER2 in BC and CRC)

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14
Q

Challenges of CAR T?

A
  • stably integrate into genome, malignant transformation.
  • clinical safety
  • ? safer alternatives
  • cost - 1/2 mill.
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15
Q

What does a tumour release when treated with RT?

A

DAMPS

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16
Q

What DAMPS are released at which stage of cell death?

A

Pre mortem - calreticulin (eat me)
Mid stage - ATP (find me)
Late stage - HMBG1 ( respond to me)

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17
Q

How does IFN type 1 release after RT?

A
  • RT causes RT phagocytosis
  • DNA detected –> cGAS –> STING
  • IFN 1/b activate DC, T cell priming etc.
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18
Q

What is the Abscopal effect?

A

Local irradiation of tumour leads to DAMPs and immune activation of tumour DAMPS and therefore reduction of distal mets.

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19
Q

What stimulated up regulation of PD-1?

A

T cell activation relases IFN -g and tumour expression of PD-1

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20
Q

What can exaggerate the abscopal effect?

A

Immune checkpoint inhibitors

fractionating

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21
Q

Why does increases Gy of RT not have the abscopal effect.

A

Possibly due to TREX 1 release which inhibitors STING activation

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22
Q

What pathway does the Abscopal effect use?

A

cGAS–> STING –> IFNa/b

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23
Q

What is the cancer stem cell (CSC) hypothesis?

Study These Flashcards
A

Not all tumour, but stem cells, have the ability to grow a tumour

24
Q

Whats the current tumour model?

Study These Flashcards
A

All the cells have the ability to develop into a cancer

25
Evidence for CSC?
- Ascities have clonal origin - few cell are able produce cancer in murine model - Stem cell can produce heterogeneous cell types - stem 'like' cell associated with poorer survival
26
Evidence against CSC?
- small collections of cell can produce tumour in murine model - Normal cell can grow tumour in melanoma (?EMT)
27
What is the EMT?
Epithelial mesenchymal transition - normal cell can transition into stem cells.
28
What is Stochastic phenotypical state transitions?
Cell types can transition between types, including stem cells.
29
Definitions of stem cells?
- Capably of self-renewal - Capable of differentiation - Respresent a distinct minority population - Initial cancer
30
What pathways are targeted to affect EMT?
Wnt Notch ADLH-1 Hedgehog
31
How does the Hedgehog pathway work?
1. hedgehog ligand inhibibit PITCH receptr 2. This stops the inhibition of Smo 3. Smo releases SUFU 4. resultant Gli leads to gene transcription
32
How does the Wnt pathway work?
1. Wnt binds to receptor 2. binding stops a destructive complex 3. B-caretinine is no longer depredated 4. gene transcription
33
How does the Notch pathway work
1. adjacent cell exposes DLL/JAG to NOTCH 2. g-secretase cleaves NICD from NOTCH 3. intracellular signalling
34
What signals regulate CSC in breast?
IL-8 IL-6 PGE2
35
What does ALDH-1 do?
- converts retinoid to retinoic acid | - indicates progenitor (stem like) cells
36
What syndrome is related to Hedge hog?
Grolins - BCC, deformity
37
What happens to radioactive decay of a nucleus (F18 to O18)
- proton transitions to neutron - Positron released and annihilates with electron - Co-linear g-photon emitted
38
What is FGD?
glucose with F18. Shows metabolically active cells.
39
what is FLT?
Thymidine with F18. 1. trapped intraceullar by phosphorylation by thymidine kinase 1 2. TK1 upregulated in Phase => Trapped in proliferating cells
40
What is PSMA?
Prostate-specific Memabrane antigen - delivers lutecium 177 (therapy) - delivers gallium 68 (tracer) For many tumours + prostate 2nd
41
What tracer can be used to detect hypoxia?
[F18] MISO
42
How does MISO work?
is chemically reduced and cannot be deoxidised in hypoxic cells leading to trapping in (tumour) cell.
43
What factors limit spatial resolution of a PET-CT?
- variation in non linear gama emision | - positron annihilation distance from source
44
What is the most common way to perform transmutation of a nucleus?
Nuetron bombardment
45
What does a cyclotron do?
Uses a magnetic and perpendicular electric field to accelerate a proton. This proton is accelerated towards a target to produce a tracer for PET-CT.
46
Why night nano bodies be used compared to antibodies?
nano-bodies have a favourable (less mass) kinetic profile. Therefore, work faster and different tracer isotopes can be used.
47
what makes a valid target?
- unmet clinical need - target drives disease - evidence of therapeutic window - evidence that patient population would benefit
48
Methods for finding a HIT drug?
HTS- high through put screening Fragmentation In Silico design
49
What are PAINS in drug development?
Pan-assay interference compounds. Appear as HITs but interfere with assay instead.
50
Advantages to point screening rather than IC50?
Cheap quick manageble data set
51
What is logD?
log10(distribution coefficient of octane and water). corrected for ionisation (P when uncorrected)
52
what drug properties does logD increase?
potency and permeability
53
what drug properties does logD decrease?
solubility metabolism protein binding toxicity
54
A decrease in LogD increases what drug properties?
solubility metabolism protein binding toxicity
55
A decrease in LogD decreases what drug properties?
potency and permeability

Oncology lecture B (4 decks)

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