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AI - Cancer Immunology > Cancer Immunotherapy > Flashcards

Cancer Immunotherapy Flashcards

1
Q

What is immunotherapy?

A

Therapeutic approaches that modulate the immune response to enhance immune cell attack of tumour cells, and to overcome the immunosuppressive tumour environment.

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2
Q

What is the crucial factor that determines the usefulness of immunotherapy?

A

Expression pattern of tumour antigens.

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3
Q

What are adoptive transfer treatments?

A

Injection of tumour-specific, tumour-infiltrating lymphocytes that have been activated ex vivo.

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4
Q

What cells were originally used for adoptive transfer?

A

Non-specific, activated lymphocytes (LAK).

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5
Q

What is cytokine therapy?

A

Injection of cytokines to enhance innate/adaptive immune responses.

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6
Q

Why is IFNa used in cytokine therapy?

A

Upregulates expression of MHC class I, adhesion molecules, and NKG2D ligands - activating NK and T cells. Promotes DC activity.

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7
Q

Give examples of when IFNa cytokine therapy is used.

A

Treatment of melanoma, kidney cancer and multiple myeloma.

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8
Q

Why is IL-2 used in cytokine therapy?

A

Used to drive differentiation of endogenous T cells.

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9
Q

Give an example of when IL-2 cytokine therapy is used.

A

Treatment of kidney cancer, and is given to adoptive transfer patients.

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10
Q

What is the disadvantage of IL-2 cytokine therapy?

A

A high dose is needed, and results in non-specific activation of T cells - can attack host tissue.

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11
Q

Describe bacterial immunostimulant therapy.

A

Injection of something the body will detect as foreign, mimicking an infection, e.g. local injection of LPS.

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12
Q

What is the aim of bacterial immunostimulant therapy?

A

In vivo stimulation of NK cells and macrophages - aiming to drive IFNy and IL-12 production from macrophages, as these cytokines stimulate the adaptive immune response.

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13
Q

Give the 3 types of serotherapy.

A
  • injection of mAb coupled to toxins, against the TSA.
  • injection of mAb that promote ADCC.
  • injection of mAb that block inhibitory signals.
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14
Q

What is rituximab?

A

Anti-CD20 antibody, used in the treatment of lymphomas and leukaemias.

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15
Q

What are the outcomes of rituximab treatment?

A
  • prevents CD20 downregulation in BCL.
  • ab binding promotes ADCC via CD16 on NK cells.
  • ab stimulates phagocytosis by macrophages.
  • forces clustering of Fc receptors on the tumour cell membrane, triggering apoptosis of the tumour cell.
  • ab binding activates the c1q complement pathway to cause tumour cell lysis.
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16
Q

How does antibody treatment promote NK cell cytotoxicity?

A

Antibodies bound to tumour antigens can be recognised by CD16, activating NK cells.

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17
Q

How can NK cells kill multiple tumour cells?

A
  • can attach to two tumour cells at once, and polarise granules towards the first cell, and then the second cell.
  • can detach from dead cells and go on to kill other targets.
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18
Q

How is there heterogeneity in NK cells?

A

Some can kill multiple tumour cells, some will only kill a few tumour cells and some will form contacts with tumour cells but are unable to kill them.

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19
Q

What is BiTE?

A

Ab composed of two single chain antibodies;

  • CD3 mAb -> binds CD3 on T cells.
  • TAA mAb -> binds tumour antigen.
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20
Q

What is the aim of BiTE antibodies?

A

Aiming to form a tight synapse between T cells and tumour cells, optimising the T cell response.

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21
Q

What is checkpoint blockade therapy?

A

Injection of antibodies that block inhibition of immune cells.

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22
Q

How can NK cell inhibition be blocked?

A

Antibody against the KIR receptor, preventing inhibition of NK cells by MHC-expressing tumour cells. NK cells can then be activated to kill tumour cells via activatory receptors, e.g. NKG2D.

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23
Q

Give an example of an anti-KIR antibody in clinical trials.

A

Lirilumab.

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24
Q

What is an effector T cell?

A

CTLA-4+ T cell.

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25
Q

What is an exhausted T cell?

A

PD1+ T cell.

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26
Q

What is the purpose of CTLA-4 and PD-1?

A

Aim to reduce T cell activation when the immune response is no longer required.

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27
Q

How does CTLA-4 inhibit T cell activation?

A

Competes with CD28 for B7 binding - giving signalling that prevents T cell activation.

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28
Q

How does PD-1 inhibit T cell activation?

A

PDL-1 (can be expressed by tumour cells), binds PD-1 and stops T cell activation.

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29
Q

Give an anti-CTLA-4 antibody.

A

Ipilulimab - used in the treatment of metastatic melanoma and some other cancers.

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30
Q

Why is Ipilulimab an expensive treatment?

A

Involves injection cycles - treatment is limited by the half life of the antibody, and reinjection is required.

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31
Q

Is Ipilulimab an effective treatment?

A

Yes - induced complete remission in melanoma patients after 100 weeks of treatment.

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32
Q

Give an anti-PD1 antibody.

A

Nivolulimab - used in the treatment of metastatic melanoma.

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33
Q

Why is anti-PD1 more commonly used in treatments than anti-CTLA4?

A

Blocking CTLA-4 is more toxic for the patient.

34
Q

Why is Nivolulimab more effective in melanoma treatment than lung/kidney cancers?

A

Melanomas are more immunogenic - release a lot of TSAs.

35
Q

Give cytokines used to activate NK cells ex vivo.

A

MMP activators, Sushi, IL-15/IL-15Ra.

36
Q

Why should alloreactive NK cells be used for adoptive transfer?

A

Mismatching KIRs - receptors from another patient won’t recognise patient MHC Class I, decreasing the chance of NK cell inhibition.

37
Q

Describe how adoptive transfer of anti-tumour lymphocytes is achieved.

A
  • Tumour mass is taken from patient -> mixed culture of tumour cells and associated immune cells.
  • T cells are isolate and plated on 96-well plates.
  • T cells activated by exposure to the mixed culture.
  • ELISA assay to test for IFNy release from activated T cells.
  • Activated T cells are expanded in culture and injected into patients.
38
Q

What are the limitations of adoptive transfer of anti-tumour lymphocytes?

A
  • Takes a week to culture cells following surgery.
  • During this time, the tumour may have changed/lost the tumour antigen.
  • Limited by the lifespan of the T cells after injection, and whether the tumour cells express PDL-1 - inhibiting exhausted T cells.
39
Q

What are the aims of CART therapy?

A

To prolong proliferation of the injected T cells, whilst also giving good recognition of the tumour antigen.

40
Q

How is CAR engineered into primary T cells?

A

Using a retroviral vector.

41
Q

What is the CAR?

A

Receptor combining antigen recognising variable regions with intracellular T cell signalling domains.

42
Q

Give T cell intracellular signalling domains used in CAR.

A

CD3 zeta chain, CD28 and 4-1BB (another costimulatory molecule).

43
Q

How is adoptive transfer of CAR-T cells achieved?

A
  • T cells harvested from patient through leukapheresis.
  • Retrovirus induces CAR expression in these T cells.
  • Culture is expanded and antibody beads are used to isolate CAR+ T cells (Takes 5 days).
  • CAR-T cells are reinjected into patients.
44
Q

What are the limitations of CAR-T therapy?

A

Very expensive, customised treatment, need to know the antigen to target, and need to know that the tumour cells are expressing this antigen.

45
Q

Give examples of antigens that CAR is being developed against.

A

WT-1, CD22, L1-CAM.

46
Q

What antigen has CAR been FDA approved for?

A

CD19 - used in treatment of B cell lymphoma.

47
Q

Why could anti-CD22 CAR be a follow on therapy for CD19 CAR?

A

Leukemic cancer cells can lose CD19 expression, whilst maintaining CD22 expression, e.g. in ALL.

48
Q

What cancers is WT-1 overexpressed in?

A

AML, NSCLC, breast, pancreatic, ovarian and colorectal.

49
Q

What cancers is L1-CAM overexpressed in?

A

Glioblastoma, lung, pancreatic and ovarian.

50
Q

Give side effects associated with CAR-T cell therapy.

A
  • Total B cell ablation.
  • Cytokine rush (mainly IL-6, also TNFa).
  • Autoimmunity.
  • Diabetes.
  • Neurotoxicity; confusion, delirium, aphasia and seizures.
51
Q

How is B cell ablation overcome in CAR-T treated patients?

A

Injection of Ig antibodies from donors, enabling patients to fight any infections encountered.

52
Q

How is IL-6 release overcome in CAR-T treated patients?

A

Injection of antibodies against IL-6, preventing the inflammatory response.

53
Q

Give methods to control CAR-T cells.

A
  • Transient expression of CAR.

- Addition of a suicide gene.

54
Q

Give examples of suicide genes used to control CAR-T cells.

A
  • iCasp9 - induces apoptosis when expressed.

- CD20 - treatment with anti-CD20 antibodies eliminates CAR T cells.

55
Q

How is transient expression of CAR achieved?

A

Cells only express CAR when given the CAR mRNA - no genome integration involved.

56
Q

Give types of cancer vaccines.

A
  • Tumour vaccines.
  • DNA vaccines.
  • Dendritic cell vaccines.
  • Anti-viral vaccines.
57
Q

What are tumour vaccines?

A

Injection of irradiated tumour cells into patients, used when the TSA has not been identified.

58
Q

What are DNA vaccines?

A

Immunisation with plasmids encoding the tumour antigen. Requires knowledge of TSA and is limited by half-life of plasmid in the body.

59
Q

What are dendritic cell vaccines?

A

Injection of DCs expressing tumour antigens, or DCs that have been loaded with tumour lysate, and present the antigens.

60
Q

How can dendritic cells be engineered to locally activate immune cells?

A

Engineered to express cytokines or costimulatory receptors.

61
Q

How do anti-viral vaccines prevent cancer?

A

Vaccination gives efficient antiviral immune response, and the body takes less time to fight the infection when acquired, meaning there is no overinflammation which could result in cancer up to 20 years after infection.

62
Q

Give examples of anti-viral vaccines.

A

Gardasil/Cervarix - vaccines against HPV types 16/18 that cause 20% of all cervical cancers.
HepB/HepC vaccines - prevent hepatocellular carcinomas.

63
Q

What cancers are linked to EBV?

A

Burkitt lymphoma, Non-Hodgkin lymphoma and Hodgkin lymphoma.

64
Q

What cancer is associated to HHV8?

A

Kaposi’s sarcoma.

65
Q

What cancer is associated to HTLV1?

A

Adult T cell leukaemia.

66
Q

What is the limitation of viral vaccines?

A

Viruses can be variant and unaffected by the vaccine - need a mix of vaccines to properly target the infection.

67
Q

How can viral infection affect tumours not normally associated to viral infection?

A

May exhaust/dampen the immune response, enabling tumours to escape immune surveillance.

68
Q

Give potential immunotherapeutic approaches for the future.

A
  • Increasing antigenicity of tumour cells.
  • Regulation of chronic inflammation, blocking IL-6 release.
  • Blocking immunosuppressive cells.
69
Q

How can the antigenicity of tumours be increased?

A

Combination of immunotherapy with radiotherapy. Radiotherapy causes apoptosis of the tumour cells, which results in the release of tumour antigen.

70
Q

Why did it take a long time for CAR-T therapy to be FDA approved?

A

Some patients developed severe inflammation in the brain, causing neurotoxicity.

71
Q

How long after injection have CAR-T cells been found in patients, and how were these identified?

A

Up to 3 years after injection - identified using RT-PCR.

72
Q

What are the consequences of cytokine release syndrome?

A

Causes patients to have high fever (IL-6 is a pyrogen) and nausea. Can lead to hypotension, tachycardia, cardiac/renal/hepatic dysfunction.

73
Q

Give evidence for the cytokine rush.

A

Patient temperature rises immediately after CAR-T injection.

74
Q

Why does the cytokine rush occur?

A

The T cell response drives inflammation, which results in the release of IL-6 from other myeloid cells, and possibly muscle and tumour cells.

75
Q

What is CRP?

A

A molecule associated with liver inflammation - high levels of CRP, and therefore liver inflammation are seen on day 2 following CAR-T injection.

76
Q

How can new tumour antigens be discovered?

A

Analysing the specificity of existing T cell responses, and identifying the target of the response, using screening strategies such as the SEREX programme.

77
Q

What does the SEREX programme do?

A

Uses the sequence of the tumour antigen and employs epitope prediction to identify relevant epitopes as candidates for vaccination.

78
Q

What are immunoassays needed for during epitope identification?

A

To check for specific interactions between the predicted epitope and the tumour antigen - by testing for activation of patient T cells using DCs loaded with the predicted epitope.

79
Q

What is required by approaches to identify tumour antigens?

A

Sequencing of patient-derived cancerous tissue, and from multiple biopsies, as well as sequencing of normal tissue.

80
Q

Why is it becoming more possible to identify patient’s tumour antigens?

A

Sequencing is becoming cheaper - but this is a still an expensive approach.

81
Q

What is a disadvantage of cytokine therapy?

A

Cannot control cytokine activity upon injection - will have a widespread systemic effect.

AI - Cancer Immunology (3 decks)

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