Mres cohort lectures Flashcards
What is a TCR modified T cell?
Autologous T cell expansion of TILS with a modified T cell for the cancer
What is a CAR T cell?
Autologous t cells which have an artificial immune receptor
How do tumour cell drive immune tolerance?
Down reg MHC Up reg FAS ligand Down reg co-stimulatory (CD80) produce immuo-supressive factors ( TGF-b, IL-6) immunosuppressive cells
What immunotherapy suppressive cells are there?
Treg
MDSC (myeloid derived sup. cells)
Tumour associated macrophages
How are TILS used?
Tumor infiltrating lymphoctyes are directly injected into tumour.
Challenges against TILS?
- work in hot tumours
- difficult to harvest from excised tumour
- inhibited by TME
Do CAR need MHC?
No
Does CAR need signals 1 and 2 for activation?
NO
How does CAR kill tumours
cytotoxic action
CAR-T cells toxicity syndromes?
Tumour lysis syndrome
Cytokine storm
Sx of cytokine storm?
hypotension
fever
Sx of tumour lysis syndrome?
metabolic complications.
- abdo pain, distension,
- Urinary (think rhabdomyolysis)
- Hypocalcaemia (thrones, grows etc.)
- Hyperkalaemia (weekness and paralysis)
What is an off target toxicity?
CAR directed at same epitope but not at tumour (HER2 in BC and CRC)
Challenges of CAR T?
- stably integrate into genome, malignant transformation.
- clinical safety
- ? safer alternatives
- cost - 1/2 mill.
What does a tumour release when treated with RT?
DAMPS
What DAMPS are released at which stage of cell death?
Pre mortem - calreticulin (eat me)
Mid stage - ATP (find me)
Late stage - HMBG1 ( respond to me)
How does IFN type 1 release after RT?
- RT causes RT phagocytosis
- DNA detected –> cGAS –> STING
- IFN 1/b activate DC, T cell priming etc.
What is the Abscopal effect?
Local irradiation of tumour leads to DAMPs and immune activation of tumour DAMPS and therefore reduction of distal mets.
What stimulated up regulation of PD-1?
T cell activation relases IFN -g and tumour expression of PD-1
What can exaggerate the abscopal effect?
Immune checkpoint inhibitors
fractionating
Why does increases Gy of RT not have the abscopal effect.
Possibly due to TREX 1 release which inhibitors STING activation
What pathway does the Abscopal effect use?
cGAS–> STING –> IFNa/b
What is the cancer stem cell (CSC) hypothesis?
Not all tumour, but stem cells, have the ability to grow a tumour
Whats the current tumour model?
All the cells have the ability to develop into a cancer
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
Evidence against CSC?
- small collections of cell can produce tumour in murine model
- Normal cell can grow tumour in melanoma (?EMT)
What is the EMT?
Epithelial mesenchymal transition - normal cell can transition into stem cells.
What is Stochastic phenotypical state transitions?
Cell types can transition between types, including stem cells.
Definitions of stem cells?
- Capably of self-renewal
- Capable of differentiation
- Respresent a distinct minority population
- Initial cancer
What pathways are targeted to affect EMT?
Wnt
Notch
ADLH-1
Hedgehog
How does the Hedgehog pathway work?
- hedgehog ligand inhibibit PITCH receptr
- This stops the inhibition of Smo
- Smo releases SUFU
- resultant Gli leads to gene transcription
How does the Wnt pathway work?
- Wnt binds to receptor
- binding stops a destructive complex
- B-caretinine is no longer depredated
- gene transcription
How does the Notch pathway work
- adjacent cell exposes DLL/JAG to NOTCH
- g-secretase cleaves NICD from NOTCH
- intracellular signalling
What signals regulate CSC in breast?
IL-8
IL-6
PGE2
What does ALDH-1 do?
- converts retinoid to retinoic acid
- indicates progenitor (stem like) cells
What syndrome is related to Hedge hog?
Grolins - BCC, deformity
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
What is FGD?
glucose with F18. Shows metabolically active cells.
what is FLT?
Thymidine with F18.
- trapped intraceullar by phosphorylation by thymidine kinase 1
- TK1 upregulated in Phase
=> Trapped in proliferating cells
What is PSMA?
Prostate-specific Memabrane antigen
- delivers lutecium 177 (therapy)
- delivers gallium 68 (tracer)
For many tumours + prostate 2nd
What tracer can be used to detect hypoxia?
[F18] MISO
How does MISO work?
is chemically reduced and cannot be deoxidised in hypoxic cells leading to trapping in (tumour) cell.
What factors limit spatial resolution of a PET-CT?
- variation in non linear gama emision
- positron annihilation distance from source
What is the most common way to perform transmutation of a nucleus?
Nuetron bombardment
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.
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.
what makes a valid target?
- unmet clinical need
- target drives disease
- evidence of therapeutic window
- evidence that patient population would benefit
Methods for finding a HIT drug?
HTS- high through put screening
Fragmentation
In Silico design
What are PAINS in drug development?
Pan-assay interference compounds. Appear as HITs but interfere with assay instead.
Advantages to point screening rather than IC50?
Cheap
quick
manageble data set
What is logD?
log10(distribution coefficient of octane and water). corrected for ionisation (P when uncorrected)
what drug properties does logD increase?
potency and permeability
what drug properties does logD decrease?
solubility
metabolism
protein binding
toxicity
A decrease in LogD increases what drug properties?
solubility
metabolism
protein binding
toxicity
A decrease in LogD decreases what drug properties?
potency and permeability
