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AI - Cancer Immunology > NK Cell Immunotherapy > Flashcards

NK Cell Immunotherapy Flashcards

1
Q

Why are NK cells useful for immunotherapy?

A
  • critical for cancer immunosurveillance
  • exist in large amounts
  • broad range of activatory/inhibitory receptors
  • potential to be used in other contexts; NK cells recognise a wide range of pathogens.
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2
Q

Give evidence for the importance of NK cells in immunosurveillance of tumours.

A
  • Mice lacking NK cells have increased incidence and progression of cancer.
  • 11 yr study of Japanese showed increased incidence of cancer in individuals with lower levels of NK cytotoxicity.
  • Infiltration of NK cells into tumours is associated with a favourable prognosis in NSCLC, CCC, and colorectal cancers.
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3
Q

Give future research questions for NK cell immunotherapy.

A

Can ex vivo expansion for adoptive transfer be done more efficiently to produce non-exhausted NK cells?
Is there a way to mobilise NK cell numbers on demand in vivo?
Can NK cell entry into tumours be improved?

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4
Q

What is the TIGIT receptor?

A

Inhibitory receptor - recognises CD155 and CD122.

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5
Q

What is the TIM-3 receptor?

A

Inhibitory receptor - recognises galectin-9 and PS.

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6
Q

Give examples of NK cell inhibitory receptors.

A

KIRs, CD94/NKG2A, TIGIT, TIM-3, PD-1

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7
Q

Give examples of NK cell activatory receptors.

A

NKG2D, NKp30, NKp44, NKp46, CD16, LIGHT.

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8
Q

What is recognised by NKp30?

A

Heparin, Heparan sulfate and proteins specific to HCMV.

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9
Q

What is recognised by NKp46?

A

Viral HAs, heparin, heparan sulfate and complement factor p.

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10
Q

What is recognised by LIGHT?

A

Recognises the herpes virus entry mediator protein.

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11
Q

Give the cytokines used to expand NK cells ex vivo.

A

IL-2, IL-12, IL-15, IL-18 and IL-21.

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12
Q

What is recognised by NKp44?

A

Viral HAs and envelope proteins, heparin and heparan sulfate, PNCA expressed on tumour cells.

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13
Q

Give the types of NK cell immunotherapy.

A
  • adoptive transfer
  • agonists of activatory receptors
  • checkpoint blockade of inhibitory receptors
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14
Q

Describe the two types of NK cell adoptive transfer.

A

Autologous - using the patients own NK cells.

Allogenic - using NK cells from a donor individual.

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15
Q

How many cells are required per treatment cycle in NK cell adoptive transfer?

A

Up to 10^11

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16
Q

What feeder cells are typically used?

A

Irradiated foetal liver stromal cells or irradiated human K562 cells.

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17
Q

Why do patients receive a low dose of IL-2 following adoptive transfer?

A

To maintain expansion of the activated NK cells upon injection.

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18
Q

Why is NK cell adoptive transfer described as a mass action effect?

A

The NK cells are not directed towards any site - hope that enough reach the tumour.

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19
Q

How can NK cells be attracted to the tumour bed following adoptive transfer?

A

By chemoattractants released in the tumour microenvironment.

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20
Q

What is the major limitation of autologous NK cell transfer?

A

Patient NK cells have KIRs that recognise the patient MHC haplotype that may be expressed by tumour cells - giving an dominant inhibitory to the activated NK cells.

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21
Q

Describe allogenic NK cell adoptive transfer.

A

Patient receives NK cells that have been expanded from a healthy donor; using either peripheral or umbilical cord blood.

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22
Q

Why must donor T cells be removed from the cell culture before reinjection?

A

These could attack the patient’s own cells.

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23
Q

Why must the patient’s own T cells be depleted?

A

Could cause graft vs host disease.

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24
Q

Describe the CAR used for NK CAR therapy.

A

Consists of intracellular signalling domains of activatory stress ligand receptors, and an Ab against the TSA.

25
Q

What is the aim of NK CAR therapy?

A

Improves efficiency of NK activation against tumour cells by providing another recognition event.

26
Q

Why should CD34+ cells from umbilical cord blood be used for NK cell CAR therapy?

A

They are easier to transduce than peripheral blood NK cells. The CD34+ CAR+ cells can then be driven to differentiate into CAR+ NK cells.

27
Q

What is the disadvantage of using peripheral cord blood NK cells for adoptive transfer?

A

Cells quickly become exhausted (PD-1+).

28
Q

Describe the exhausted phenotype of NK cells.

A

Decreased cytotoxicity, decreased cytokine expression, significantly decreased Eomes expression and increased PD-1 expression.

29
Q

What is CD34 a marker for?

A

Stem cells and blood cell progenitors.

30
Q

How can NK cells be derived from umbilical cord blood?

A

CD34+ in UCB can be driven to differentiate to give mature NK cells.

31
Q

Give the advantages of UCB-derived NK cells as opposed to peripheral blood NK cells.

A
  • UCB-derived cells are easier to transduce with the CAR receptor.
  • UCB-derived NK cells can be frozen with a viability of 50%.
  • UCB-derived NK cells do not become exhausted.
32
Q

Why do UCB-derived NK cells not become exhausted, but peripheral blood NK cells do?

A

The current assumption is that these cells do not become exhausted as they were originally undifferentiated cells – the lab has replicated differentiation to the same stage as mature peripheral blood NK cells.
When using peripheral blood NK cells for adoptive transfer, they are super activated in the lab, and were previously differentiated, meaning that they become exhausted sooner.

33
Q

What is the advantage of cryopreservation of NK cells?

A

Enables storage of NK cells between treatment cycles.

34
Q

Why are patients given chemotherapy before receiving adoptive transfer of NK cells?

A

To create space in the haematopoietic niches for these introduced cells to graft transiently.

35
Q

Why do adoptively transferred NK cells only graft transiently in the bone marrow?

A

The mature NK cells will leave the bone marrow to act upon the tumour and will eventually be depleted - this graft is not a source of new NK cells.

36
Q

Give the advantages of CAR-NK over CAR-T therapy.

A
  1. No problems with autoimmunity - NK cells do not have antigen-specific memory.
  2. No need for suicide genes - mature NK cells only have a lifespan of 2 weeks.
  3. Downregulation of TSAs does not render CAR-NK cells useless - have other recognition methods.
  4. Cytokines released following CAR-NK injection are less harmful than IL-6.
37
Q

Why can melanoma patients develop vitiligo following CAR-T treatment?

A

Develop autoimmunity against melanocytes, so vitiligo develops where melanocytes are killed, and there is areas of no melanin production.

38
Q

What is rituximab and when is it used?

A

Ab against CD20 - used in the treatment of lymphomas and leukaemias.

39
Q

What is trazutumab and when is it used?

A

Ab against Herceptin-2 - used in the treatment of Her2+ breast cancers.

40
Q

What is cetuximab?

A

Ab against EGF - has anti-angiogenic effects as well as promoting ADCC.

41
Q

When are monoclonal antibodies most effective?

A

When there are high levels of NK cell activity.

42
Q

What is the major issue associated with stimulating the ADCC response? How might this be overcome?

A

NK cells can lose CD16 expression upon activation through ADAM17 metalloprotease activity. Can be overcome by MMP inhibitors.

43
Q

Why are breast cancers sometimes resistant to trazutumab?

A

The tumour cells upregulate ADAM17 to promote metastasis, causing NK cells in the tumour bed to lose CD16.

44
Q

Describe BiKE antibodies.

A

Single chain variable region of Ab against CD16 combined with the single chain variable region of Ab against the TAA.

45
Q

What is the aim of BiKE/TriKE antibodies?

A

To bring NK cells into close proximity with tumour cells, enhancing their ability to recognise and kill tumour cells.

46
Q

What is the advantage of only using single chain variable regions of each antibody to produce BiKE/TriKE?

A

Produces a smaller antibody which gives better biological distribution - gives better entry into solid tumours.

47
Q

Why might some patients not respond well to treatments that promote ADCC?

A

Some patients have a polymorphism in the CD16 gene, that means their CD16 binds the Fc region of antibodies less strongly.

48
Q

What is the aim of checkpoint blockade therapy?

A

Transient dampening of the inhibitory signals, improving the NK cell response.

49
Q

Give examples of antibodies against NK cell inhibitory receptors.

A
  • IPH2101; binds KIR2DL-1/KIR2DL-2/KIR2DL-3 with high affinity. Phase I trial showed the Ab was well tolerated b AML and MM patients, but Phase II showed no clinical efficacy.
  • Lirulimab; anti-KIR, in phase I trials.
  • Monalizumab; anti-NKG2A, in development.
50
Q

What are REV-ERBa and REV-ERBb?

A

TFs that block E4bp4 activity.

51
Q

Why can REV-ERB be drugged, despite being a TF?

A

Binds a haem ligand for its activity - meaning there is a binding pocket that could be drugged.

52
Q

What happens when HPCs are driven to become NK cells, in the presence of an REV-ERB antagonist?

A

Increased NK cell production, due to there being no inhibition of E4bp4.

53
Q

What happens when HPCs are driven to become NK cells, in the presence of an REV-ERB agonist?

A

Repression of NK cell production.

54
Q

What happens when UCB-derived CD34+ cells are driven to become NK cells in the presence of the REV-ERB antagonist?

A

Faster NK cell production.

55
Q

Why is it important to be able to produce NK cells and reintroduce them into patients as quickly as possible during adoptive transfer?

A

To minimise any chance of exhaustion.

56
Q

What happens if Notch signalling is switched on for a limited time early on in NK cell development?

A

Increased NK cell production.

57
Q

Give evidence for the role of Notch signalling in NK cell development.

A

E4bp4 -/- give no NK cell production. Addition of Notch ligands rescues this if given early on and for a short period of time.
Notch ligands accelerate the production of mature NK cells from CD34+ cells.

58
Q

How could enhancing NK cell cytotoxicity be combined with checkpoint blockade?

A

Could use CRISPR/Cas9 to knock out inhibitory receptor genes in CD34+ derived NK cells - activity would be enhanced upon injection due to the lack of inhibitory signal.

AI - Cancer Immunology (3 decks)

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