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Therapeutic Immunology > T Cell Therapeutics > Flashcards

T Cell Therapeutics Flashcards

1
Q

What is preparation of CAR T cells?

A

Taking T cells out of someone’s body
Purify and magnetically store for CD4 and CD8 T cells
Transfect a vector into those T cells that express chimeric antigen receptor - transduce them normally with a lentivirus
Infused back into patient to attack cell it is binding to

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2
Q

What is a chimeric antigen receptor?

A

Normally a single chain Fv (a single antibody heavy and light chain joined together into a single protein) linked onto a membrane component to embed into the membrane , then link to set of activating domains

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3
Q

What activating domains did first generation CAR-T cells have?

A

ITAM related to ZAP70 which is related to signalling from T cell receptor

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4
Q

What do new generation CAR T cells have as activating domains?

A

Have additional co stimulatory domains as ZAP 70 on its own wasn’t sufficient

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5
Q

What were the first approvals for CAR-T cells all targeting in 2017?

A

Blood based tumours not solid tumours

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6
Q

What is the black box warning for CAR-T cells?

A

Severe risk of side effects e.g. cytokine release syndrome, neurotoxicity

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7
Q

Why do CAR-T cells have high success rates?

A

They hang around so if any cancer cells escape first wave, they are likely to be targeted later on

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8
Q

How can we prevent cytokine release syndrome?

A

Have antibdoies that can mop up high levels of TNF alpha, IL-1 beta and IL-6 etc.

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9
Q

What has been done to help the issue of balancing survival v exhaustion?

A

Changes made in costimualtory molecules, can change the way T cells behave

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10
Q

What is the problem with viral integration site

A

Can affect other genes, and proliferation. Lentiviruses are less problematic than other retroviruses but can still have issues

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11
Q

What is the problem with memory CAR-T cells?

A

Want some cells in effector memory pool that can be reactivated in future for sustaining CAR-T survival in patients long term

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12
Q

What does stimulatory domain 41BB do?

A

Slower expansion of cells, means they are more durable

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13
Q

What does stimulatory molecule CD28 do?

A

Fast expansion, less durable

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14
Q

What is the issue with resistance around CAR-T cells?

A

Avoiding resistance is an issue

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15
Q

What does CD40L accessory molecule do?

A

Facilitates T cells memory formation and induces increased immunogenicity on tumour cells

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16
Q

What does ICOSL do?

A

Enhances PI3K signalling pathwya and upregualted the expression of Bcl2

17
Q

What does IL-7 do in CAR-T cells

A

Inhibits T cells apoptosis and exhaustion

18
Q

what is the problem with CAR-T cells getting to the site?

A

Normal T cells get to the site thorugh other cells producing chemokines, then once it is there has peptides and MHC that it recognises to become activated
Tumours might not necessarily do this, therefore how you get T cells into a tumour, is by finding a reason for the T cell to want to go into the tissue in the first place

19
Q

What does IL-12 do in CAR-T cells?

A

Mitigates Treg-suppression and reprogram tumour-assocaited macrophages and dendritic cells

20
Q

What is anakinra?

A

Il-1 receptor antagonist

21
Q

What is tociluzimab?

A

IL-6 receptor blocker

22
Q

What is lenzilumab?

A

GM-CSF binder

23
Q

What does CD28 costimualory molecule do?

A

Facilitates full and sustained T cell activation, growth and survival

24
Q

What does 4-1BB co stimulatory molecule do?

A

Be assocaited with more anti-apoptotic proteins and reduced T cells exhaustion

25
Q

what does ICOS co stimulatory molecule do?

A

Presents the characteristics of Th17 cells with increased expression of Il-17A, IL-17F, and IL22 following antigen recognition

26
Q

What is the problem with genetic loss of antigen?

A

If tumour cells start to lose the target molecule that you are working with then CAR-T cells can no longer see those tumour cells

27
Q

What is the problem with CAR transduction of tumour?

A

Because you normally take these T cells out the patient themselves, if you have put some vector into tumour cells, then you can have CAR tumour cells whihc can mask and block off ability of CAR T cells to see the antigen

28
Q

What is trogocytosis?

A

T cell can itself remove antigen, means T cell cna interact with tumour cell but instead of killing it, can have antigen transfer to surface of T cell and this decreases antigen on tumour cell and makes it difficult to see how T cells can target required cells

29
Q

What is the problem with loss of death receptor signalling on tumour cells?

A

Mutaitons in cells can take away ability to respond to cell death triggers, lose ability to kill tumour cell well

30
Q

What is the problem with immunosuppressive tumour microenvironment?

A

If you have a solid tumour, often find environment is immunosuppressive. Don’t turn on and activate T cells and other immune cell to cause damage, if anything it is the other way round to try and stop them

31
Q

How can we improve CAr-T cell performance?

A

Making small alginate polymer, porous but contains lentiviruses, some cytokines and everything it needs. So when T cells went in there, they would get ransfected by virus and stimulated. Can all be done in vivo

32
Q

What is good about alginate polymer?

A

Doesn’t produce all cells at once which reduces risk of things likecytokine release syndrome

33
Q

What do you have to ensure with alginate polymer?

A

Make sure vectors only express in T cells under certain conditions, this reduces likelihood of your tumour cells expressing chimeric antigen receptor

34
Q

How can you improve CAR-T cells for solid tumours?

A

Have to start with T cells that have already infiltrated that tumour so need to take a biopsy and isolate specific T cells. Find those which are cytotoxic
So instead of taking T cells at random out of bloodstream, take ones specifically found in the tumour

35
Q

What are some of the ways in which next-generation CAr-T cells can be improved?

A

Bivalent CAR/ LINK CAR - two single chain Fvs together, can make things wider in specific or so that you have to link both to activate it, making it more specific
SynNotch - first target is primer, second recognises after priming
SNIP CAR - being able to turn off CAr T cells
HLAs - can get immune system to have a blind spot to that particular cell expressing HLA
Tethered - have tethered cytokine by peptide linker, can actually stimulate receptors on that CAR-T cell

36
Q

What are benefits of CAR-NK cells?

A

Good tumour infiltrating capability
Can kill if they recognise antibdoies, cytokines, and through perforins and granzymes
Kill other cells first without being primed
Reduces risk of graft v host disease
CD19 works just as well on an NK cell as it would on T cell

Therapeutic Immunology (13 decks)

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