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Oncology lecture B > Mres cohort lectures > Flashcards

Mres cohort lectures Flashcards

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?

A

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

24
Q

Whats the current tumour model?

A

All the cells have the ability to develop into a cancer

25
Q

Evidence for CSC?

A
  • 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
Q

Evidence against CSC?

A
  • small collections of cell can produce tumour in murine model
  • Normal cell can grow tumour in melanoma (?EMT)
27
Q

What is the EMT?

A

Epithelial mesenchymal transition - normal cell can transition into stem cells.

28
Q

What is Stochastic phenotypical state transitions?

A

Cell types can transition between types, including stem cells.

29
Q

Definitions of stem cells?

A
  • Capably of self-renewal
  • Capable of differentiation
  • Respresent a distinct minority population
  • Initial cancer
30
Q

What pathways are targeted to affect EMT?

A

Wnt
Notch
ADLH-1
Hedgehog

31
Q

How does the Hedgehog pathway work?

A
  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
Q

How does the Wnt pathway work?

A
  1. Wnt binds to receptor
  2. binding stops a destructive complex
  3. B-caretinine is no longer depredated
  4. gene transcription
33
Q

How does the Notch pathway work

A
  1. adjacent cell exposes DLL/JAG to NOTCH
  2. g-secretase cleaves NICD from NOTCH
  3. intracellular signalling
34
Q

What signals regulate CSC in breast?

A

IL-8
IL-6
PGE2

35
Q

What does ALDH-1 do?

A
  • converts retinoid to retinoic acid

- indicates progenitor (stem like) cells

36
Q

What syndrome is related to Hedge hog?

A

Grolins - BCC, deformity

37
Q

What happens to radioactive decay of a nucleus (F18 to O18)

A
  • proton transitions to neutron
  • Positron released and annihilates with electron
  • Co-linear g-photon emitted
38
Q

What is FGD?

A

glucose with F18. Shows metabolically active cells.

39
Q

what is FLT?

A

Thymidine with F18.

  1. trapped intraceullar by phosphorylation by thymidine kinase 1
  2. TK1 upregulated in Phase

=> Trapped in proliferating cells

40
Q

What is PSMA?

A

Prostate-specific Memabrane antigen

  • delivers lutecium 177 (therapy)
  • delivers gallium 68 (tracer)

For many tumours + prostate 2nd

41
Q

What tracer can be used to detect hypoxia?

A

[F18] MISO

42
Q

How does MISO work?

A

is chemically reduced and cannot be deoxidised in hypoxic cells leading to trapping in (tumour) cell.

43
Q

What factors limit spatial resolution of a PET-CT?

A
  • variation in non linear gama emision

- positron annihilation distance from source

44
Q

What is the most common way to perform transmutation of a nucleus?

A

Nuetron bombardment

45
Q

What does a cyclotron do?

A

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
Q

Why night nano bodies be used compared to antibodies?

A

nano-bodies have a favourable (less mass) kinetic profile. Therefore, work faster and different tracer isotopes can be used.

47
Q

what makes a valid target?

A
  • unmet clinical need
  • target drives disease
  • evidence of therapeutic window
  • evidence that patient population would benefit
48
Q

Methods for finding a HIT drug?

A

HTS- high through put screening
Fragmentation
In Silico design

49
Q

What are PAINS in drug development?

A

Pan-assay interference compounds. Appear as HITs but interfere with assay instead.

50
Q

Advantages to point screening rather than IC50?

A

Cheap
quick
manageble data set

51
Q

What is logD?

A

log10(distribution coefficient of octane and water). corrected for ionisation (P when uncorrected)

52
Q

what drug properties does logD increase?

A

potency and permeability

53
Q

what drug properties does logD decrease?

A

solubility
metabolism
protein binding
toxicity

54
Q

A decrease in LogD increases what drug properties?

A

solubility
metabolism
protein binding
toxicity

55
Q

A decrease in LogD decreases what drug properties?

A

potency and permeability

Oncology lecture B (4 decks)

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