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A Haematology and Immunology > Immunotherapy > Flashcards

Immunotherapy Flashcards

1
Q

What is immunotherapy?

A
  • A therapy to control the immune system

- In general treatment of immune disorders is immunosuppressive or immunomodulatory

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2
Q

What is acute rejection associated with immunologically?

A

T cell responses that mediate immune cell infiltration into the graft and effect its rejection

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3
Q

What are the types of rejection?

A
  • Hyperacute
  • Acute
  • Chronic
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4
Q

What is the pathophysiology of hyperacute rejection?

A

Preformed antibodies react with vascular endothelium and activate complement which triggers rapid intravascular thrombosis and necrosis of the vessel wall

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5
Q

What is the pathophysiology of acute rejection?

A
  • CD4 and CD8 T lymphocytes are reactive with alloantigens on endothelial cells and parenchymal cells mediate damage to these cell types
  • Alloreactive antibodies formed after engraftment may also contribute to parnechymal and vascular injury
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6
Q

What is the pathophysiology of chronic rejection?

A
  • With graft arteriosclerosis
  • Injury to the vessel wall leads to intimal smooth muscle cell proliferation and luminal occlusion.
  • This lesion may be caused by a chronic inflammatory reaction to alloantigens in the vessel wall
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7
Q

What are anti-rejection drugs?

A
  • A method of inhibiting T cell activation to treat graft rejection
  • Example: Cyclosporin FK506 causes dephosphorylation of calcineurin
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8
Q

Give examples of active adaptive immunity.

A
  • Infection or exposure

- Immunisations

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9
Q

Give examples of passive adaptive immunity?

A
  • Placental transfer of IgG
  • Colostral transfer of IgA
  • Immunoglobulin therapy or immune cells
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10
Q

Give examples of passive immunity.

A
  • Snake or spider bites, scorpion or fish stings: Passive infusion of antibody specific for the toxin
  • Hypogammaglobulinaemia: primary or secondary: Infusion of y-globulins to reduced infection
  • Rabies immunoglobulins ‘post exposure prophylaxis’ together with vaccination
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11
Q

Give examples of immunoglobulins for post-exposure prophylaxis.

A

Human normal immunoglobulin (HNIG)

  • Hepatitis A
  • Measles
  • Polio
  • Rubella

Specific immunoglobulins

  • Hepatitis B
  • Rabies
  • Tetanus
  • VZV
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12
Q

What groups is IVIg appropriate for?

A
  • As replacement therapy in patients with primary or secondary antibody deficiency
  • As immune modulating therapy in certain inflammatory or autoimmune disorders
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13
Q

What conditions is IVIg licensed for?

A
  • Primary immunodeficiency
  • Wiskott Aldrich syndrome
  • IgG subclass deficiencies with recurrent infections
  • Idiopathic thrombocytopenic purpura
  • Kawasaki disease
  • Common variable immunideficiency
  • Multiple myeloma/CLL
  • Children with HIV
  • Guillain-Barre syndrome
  • Allogenic bone marrow transplant
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14
Q

What is IVIg?

A
  • Plasma-derived IgG is a key biologic for replacement therapy in primary and secondary immunodeficiency disorders (also autoimmune)
  • It is harvested from donated blood
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15
Q

How is IVIg administered?

A
  • Polyclonal IgG preparation usually given intravenously (IVIg) but can also be applied subcutaneously (SCIg)
  • Very high dose 1-3g/Kg
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16
Q

How is IVIg prepared?

A
  • Harvested from donor blood

- Pooled from thousands of donors

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17
Q

What problems are associated with Ig therapy?

A
  • Adverse reactions during infusion

- Transmission of infection (in particular hepatitis C)

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18
Q

How is transmission of infection in Ig therapy prevented?

A
  • Donor blood samples are now routinely screened for hep B, hep C and HIV
  • Viral inactivation measures are now routinely incorporated into all immunoglobulin manufacturing processes
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19
Q

What are the different types of immunotherapy?

A
  • Direct (targeted)

- Indirect

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20
Q

What is direct immunotherapy?

A

Antibodies or anitibody related fragments that detect an antigen on the tumour cell and destroy the target either by recruiting immune cells or by delivering a toxin or radioisotope to it

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21
Q

What is the target in directed immunotherapy?

A

Tumour

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22
Q

Give examples of types of direct immunotherapy.

A
  • Monoclonal antibodies
  • Chimeric antigen receptors (CARs)
  • Bi-specific antibodies
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23
Q

What is indirect immunotherapy?

A

-The immune system is activated rendering it able to seek and destroy tumour cells

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24
Q

What is the target in indirect immunotherapy?

A

The immune system

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25
Q

Give examples of types of indirect immunotherapies.

A
  • Tumour vaccines
  • Dendritic cell vaccines
  • Adoptive cell transfer
  • Cytokine therapies
  • Checkpoint inhibitor therapies
  • Stimulatory antibodies
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26
Q

What are cytokines?

A

Cytokines are cell derived, low molecular weight peptides which exert local effects on the cells which secreted them (autocrine effects) or on cells in the immediate surrounding area (paracrine).

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27
Q

What do cytokines bind to?

A

-They bind to specific cell surface receptors and can affect cell proliferation, differentiation & growth.

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28
Q

What are the major groups of defined cytokines?

A
  • Interleukins
  • Interferons
  • Colony stimulating factors
  • Tumour necrosis factors
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29
Q

What can cytokine therapy involve?

A
  • Production and administration of an in-vitro produced recombinant cytoine
  • Production of factors which will interfere with the activity of naturally produced cytokines
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30
Q

What factors can be given to interfere with the activity of naturally produced cytokines?

A
  • Monoclonal antibodies directed against cytokine molecules or against cytokine receptors
  • Small peptides resembling the cytokine itself but which are inactive and can block access of the cytokine to the cell surface receptors
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31
Q

What is cytokine therapy designed to do?

A

It is designed to inhibit the activity of harmful cytokines or enhance the activity of beneficial cytokines

32
Q

Cytokine Therapy

What does IL1/TNF (pro-inflammatory cytokines) do?

A

Decreased activity in rheumatoid arthritis and septic shock

33
Q

Cytokine Therapy

What does IL2(T cell activating cytokine) do?

A
  • Decreased activity in autoimmune disease and transplant rejection
  • Increased activity in some immune deficiency disorders and tumour therapy
34
Q

Cytokine Therapy

What does IFNa do?

A
  • Antiviral in hepatitis C

- Anti-neoplastic in hairy cell leukaemia

35
Q

Cytokine Therapy

What does IFNy do?

A

Increased phagocyte intracellular killing activity in chronic granulomatous disease

36
Q

What type of response will immunisation with an antigen typically lead to?

A

Polyclonal response

37
Q

What is a polyclonal response?

A
  • Many different B cell clones will generate antibodies specific for the antigen
  • A number of epitopes will be bound by antibody
  • Antibodies with different variable regions bind multiple epitopes
38
Q

What is the process of monoclonal response?

A
  • Immunisation
  • Fusion and immortalisation of B cells
  • Isolation and screening
  • Expansion of desired hybidroma
39
Q

Give examples of types of monoclonal antibodies.

A
  • Murine
  • Chimeric
  • Humanised
  • Human
  • Fragment
40
Q

What is the problem with manufacturing monoclonal antibodies?

A
  • Up until recently it has been difficult to produce human monoclonal antibodies in vitro
  • Monoclonal used clinically are of mouse/rat origin
41
Q

What are the problems associated with mouse/rat derived monoclonal antibodies?

A
  • Adverse reactions on administration
  • Poor efficacy of the antibodies as murine or rate antibodies do no interact with human immune effector mechanisms such as complement or Fc portion very efficiently
42
Q

What is the solution to producing monoclonal antibodies?

A

The partial solution is to humanise the mouse/rat antibodies by cleaving off part of the monoclonal and replacing it with part a human immunoglobulin molecule

43
Q

What is the first line treatment for non-Hodgekin’s lymphoma?

A

Rituximab

44
Q

What is rituximab specific for?

A

Specific for the CD20 molecule on the cell surface of a small sub-population of B cells

45
Q

Why is rituximab considered a crossover monoclonal antibody?

A

Originally developed for NHL and lymphoma but now found to have highly beneficial effects in rheumatoid arthritis and probably systemic lupus erythematosus (SLE)

46
Q

What is Infliximab used for?

A
  • Rheumatoid arthritis
  • Ankylosing spondylitis
  • Crohn’s disease
  • Ulcerative colitis
47
Q

What is infliximab?

A

Chimeric antibody that blocks the function of tumour necrosis factor alpha (TNF)

48
Q

What is TNF?

A

Pro-inflammatory cytokine that stimulates an acute phase reaction

49
Q

What is Herceptin used for?

A

Human growth epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer

50
Q

What is the action of Herceptin?

A

The antibody binds HER2 on cancer cells and marks them out for destruction by the immune system

51
Q

What percentage of breast cancers are associated with HER2?

A

15-20%

52
Q

What is the action of pertuzumab?

A

Anti-Her2 antibody

-Directed at the dimerization domain of HER2 (disruption of dimer formation)

53
Q

What do checkpoint inhibitors do?

A

Checkpoint inhibitor antibodies unlock the gateway to the adaptive immune system
They have powerful anti-tumour responses but potential for immune related adverse effects

54
Q

How are dendritic cell vaccines administered?

A
  • Take a blood sample from patient
  • Culture cells in vitro with cytokines that promote APC function
  • Transfuse patients with APC after uptake of tumour antigen
55
Q

What are CAR T cells engineered to express?

A

Antigen-targeted receptors specific for tumour antigens.

56
Q

What is the target for CAR T cells in glioblastoma?

A

IL13Ra2

57
Q

How does CAR T cell therapy work?

A
  • CAR includes an antigen-binding domain fused to a transmembrane domain followed by T-cell activation domains associated with the T-cell receptor (TCR).
  • A T cell modified with a CAR is endowed with a new antigen specificity, and binding its antigen supports T-cell activation and killing of the target cell.
58
Q

Give examples of established/standard immunosuppressive/ immunomodulation drugs

A
  • Corticosteroids
  • Azathioprine
  • Cyclophosphamide
59
Q

Give examples of ‘newer’ immunosuppressive/ immunomodulation drugs.

A
  • Cyclosporin and tacrolimus
  • Sirolimus
  • Mycophenolic acid
60
Q

How do corticosteroids work?

A
  • Affect both T & B cell function.

- Drugs bind to cytoplasmic receptors and are transported to the nucleus where expression of various genes is modified.

61
Q

What do corticosteroids have major effects on?

A
  • Cytokine networks,
  • Inflammation (particularly prostaglandin mediated inflammation),
  • T cell & monocyte function
  • Transit & circulation of immunologically active cells.
62
Q

What is azathioprine?

A
  • Purine analogue which inhibits DNA synthesis. Inhibits T & Natural Killer cell functions.
  • Anti-inflammatory.
63
Q

What is azathioprine usually used in combination with?

A

Usually used in combination with steroid to decrease requirement for large doses of steroid.

64
Q

What is cyclophosphamide?

A
  • Alkylating agent which interferes with DNA synthesis.

- Little anti-inflammatory activity and is therefore generally given in combination with steroid.

65
Q

What is cyclophosphamide useful for?

A

Suppressing B cell activity and antibody production, particularly autoantibody production.

66
Q

What are cyclosporin and tacrolimus?

A
  • Fungal products.

- Both are pro-drugs which require to bind to cytoplasmic receptors to become active.

67
Q

What are the actions of cyclosporin and tacrolimus

A
  • Involved in modulation and down-regulation of various genes, particularly transcription of interleukin-2 gene.
  • As a result major immune suppressive effects are on T cells (especially Th cells) and Natural Killer cells.
68
Q

What is sirolimus?

A
  • A drug used for many years in treatment of psoriasis, now finding a more general role in immune suppression.
  • Principle action is to decrease IL-2 production by TH cells
69
Q

What is mycophenolic acid used for?

A

-Mainly used in transplant rejection, Crohn’s Disease (and possibly also in some systemic autoimmune diseases such as SLE, ITP, Wegeners).

70
Q

What is mycophenolic acid?

A
  • Inhibitor of purine synthesis.

- Prevents T cell proliferation, antibody production and leucocyte migration.

71
Q

What is the mechanism of therapies which disrupt adhesion molecule function?

A
  • Use of monoclonal antibodies against adhesion molecules present either on immune cells or endothelium or against the ligands for adhesion molecules.
  • May also be achieved through designing peptides which, like monoclonal antibodies, can bind to adhesion molecules or their ligands and prevent them functioning effectively.
72
Q

Give an example of mediator antagonism.

A

Antihistamine drugs that block H1 receptors in type 1 hypersensitivity reactions

73
Q

What is plasma exchange/plasmapheresis commonly used in?

A

Management of some autoimmune disorders which involve formation of autoantibodies or immune complexes. -Myasthenia gravis

  • Goodpasture’s
  • Systemic vasculitis

Usually in combination with additional immunosuppressive measures such as steroid and cytotoxic drug

74
Q

What happens in plasma exchange?

A
  • The patients plasma is filtered off ex-vivo in a special centrifuge apparatus which ensures that cellular elements are not removed from the blood.
  • At the same time normal donor plasma is given back to the patient to replace that being taken of
75
Q

What happens in plasmapheresis?

A

-In plasmapheresis albumin solutions are used to replace the volume of plasma being removed rather than human plasma itself being given back.

76
Q

What are the possible mechanisms behind plasma exchange/plasampheresis?

A
  • Simple removal of circulating antibodies or immune complexes from the circulation
  • (In plasma exchange) replacement of plasma factors such as complement proteins
  • Control proteins which have been consumed as part of the disease process.

A Haematology and Immunology (20 decks)

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