immunotherapy

Question 1

what are the different immunosuppressive strategies

Answer 1

general immunosuppresive strategies

allergy and AI disease

blanket immunosuppression

opportunistic infection

strong need to develop tailored therapies that target the specific immune response but leave the rest of the immune system free to fight disease

Question 2

immunosuppression for allergy

Answer 2

anti-histamine to prevent allergic response

corticosteroids for severe allergy

anti-IgE, leukotriene antagonists to prevent bronchial constriction in asthma

Question 3

what is a risk with blanket immunosuppression

Answer 3

opportunistic infections

Question 4

why is cyclosporin so important in transplantation

Answer 4

major step forward in transplant survival

esp for cardiac transplant

Question 5

why is T cell suppression important in transplants

Answer 5

by suppressing the T cell response you can prevent acute rejection

e.g. cyclosporin, rapamycin

Question 6

how does cyclosporin work

Answer 6

calcineurin inhibitor

prevents IL-2 production by the T cell

Question 7

how does rapamycin work

Answer 7

targets mTOR (mechanistic target)

targets IL-2 uptake by the T cell

Question 8

what are the different types of immunty

Answer 8

Question 9

how does natural active immunity work

Answer 9

person is infected with microbe

days-wks later will make a response - potent adaptive immune response

T cells and antibodies against the pathogen

develop ‘memory’ for that specific pathogen

Question 10

how does passive immunity work

Answer 10

receive the antibody for a microbe from another individual

doesn’t result in memory against the pathogen as there has been no active immune response

Question 11

examples of passive immunity

Answer 11

snake/spider bites, scorpion/fish stings - passive infusion of antibody specific for the toxin

hypogammaglobulinaemia - 1y or 2y infusion of gamma globulins to reduce infection

rabies immunoglobulin - post-exposure prophylaxis together w/ vaccination

Question 12

immunoglobulin for post-exposure prophylaxis and what diseases are they given for

Answer 12

human normal immunoglobulin (HNIG):

• hep A
• measles
• polio
• rubella

specific immunoglobulins:

• hep B
• rabies
• tetanus
• VZV

Question 13

what conditions is intravenous immunoglobulin used for

Answer 13

biologic therapy for 1y and 2y immune deficiencies and some AI disorders

Question 14

what is IVIg

Answer 14

plasma derived IgG used for replacement therapy for

polyclonal IgG preparation usually given IV but can also be given SC

very high dose - 1-3g/kg

pooled from several thousand donors

Question 15

what is direct (targeted) immunotherapy

Answer 15

antibodies or antibody 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

targets tumours

recruit pro-inflammatory cells to kill tumour cells

Question 16

what is indirect immunotherapy

Answer 16

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

targets immune system

Question 17

what are ADCs

Answer 17

antibody drug conjugates

Question 18

examples of direct immunotherapy

Answer 18

monoclonal antibodies

chimeric antigen receptors (CARs)

Bi-specific antibodies

-

Question 19

what do bi-specific antibodies do

Answer 19

recognise a targeted antigen on a tumour cell

also have another target on immune cells for example - boosts immune cell activity set by specific antibodies

Question 20

examples of indirect immunotherapy

Answer 20

tumour vaccines

dendritic cell vaccines

adoptive cell transfer

cytokine therapies

checkpoint inhibitor therapies

stimulatory antibodies

Question 21

what are dendritic cell vaccines

Answer 21

highly potent immune cells

can stimulate immune responses very effectively

combine tumour antigens w/ dendritic cells to drive T cell responses

Question 22

what is adoptive cell transfer

Answer 22

cell transfer therapies where the cells have been trained to generate immune responses against the tumour antigens

Question 23

what are cytokine therapies and what are they used for

Answer 23

immunomodulatory cytokines to activate anti-tumour immunity

pegylated IFN-alpha, IL-2, GM-CSF (last one is for cancer recovery to boost neutrophil levels)
- pegylated = much longer serum half life

used in specific cancers

pegylated is an effective anti-viral IFN-alpha therapy and used in melanoma

Question 24

what is a polyclonal response

Answer 24

immunisation w/ antigen will typically lead to a polyclonal response

many different B cell clones will generate antibodies specific for the antigen

a number of epitopes will be bound by antibody

antibodies w/ different variable regions bind multiple epitopes

not that useful in clinical practice

Question 25

how are monoclonal antibodies produced

Answer 25

immunisation fusion and immortalisation of B cells isolation and screening expansion of desired hybridoma

Question 26

what are car T cells

Answer 26

combination of antibody and T ell used with multiple myeloma as a treatment

Question 27

types of antibodies used in therapeutic monoclonal antibodies

Answer 27

``` human humanised - GE antibodies chimeric - mix of mouse and human fragment - part antibody, part extracellular receptor murine - mouse ```

Question 28

what cancer is rituxan (rituximab) a first line treatment for

Answer 28

non-Hodgkins lymphoma

Question 29

how does rituximab work

Answer 29

specific for CD20 molecule on the cell surface of a small sub-population of B cells wipes out most of B cell population by recruiting macrophages and NK cells doesn't cause opportunistic infection

Question 30

what other diseases can rituximab be used to treat

Answer 30

highly beneficial in RA and SLE

Question 31

what type of therapy is infliximab

Answer 31

anti-TNF

Question 32

what is infliximab used to treat

Answer 32

RA ankylosing spondylitis crohn's disease ulcerative colitis

Question 33

how does infliximab work

Answer 33

chimeric antibody that blocks the function of tumour necrosis factor alpha

Question 34

what is TNF and what does it stimulate

Answer 34

pro-inflammatory cytokine stimulates an acute phase reaction

Question 35

what is herceptin - trastuzumab - used for

Answer 35

treatment of HER2 +ve metastatic breast cancer (human epidermal growth factor receptor 2) previously sufferers had a very poor prognosis

Question 36

how does herceptin - trastuzumab work

Answer 36

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

Question 37

what % of breast cancers are HER2+ve

Answer 37

15-20%

Question 38

example of new anti-HER2 antibodies and how they work

Answer 38

pertuzumab directed at the dimerisation domain of HER2 - disruption of dimer formation disrupts signalling complex and signalling to the cell and prevents the cancer cell from growing uncontrollably

Question 39

what is Skyrizi - risankizumab - used to treat

Answer 39

plaque psoriasis trials in crohn's and psoriatic arthritis are ongoing

Question 40

what is the target for risankizumab and what type of antibody is it

Answer 40

IL-23 p19 subunit IgG1 humanised

Question 41

how does risankizumab work

Answer 41

selectively blocks IL-23 by binding to the p19 subunit IL-23 - cytokine involved in inflammatory processes and thought to be linked to a number of chronic immune mediated diseases

Question 42

what are checkpoint inhibitor antibodies and what do they do

Answer 42

unlock the gateway to the adaptive immune system powerful anti-tumour responses potential for immune related adverse effects

Question 43

example of anti-CTLA 4 antibody

Answer 43

ipilimumab

Question 44

how do checkpoint inhibitor antibodies work e.g. anti CTLA-4 antibodies

Answer 44

dendritic cell (green) provides into to T cells about tumour antigens MHC = tissue type molecule, presents yellow peptide antigen (from tumour cell) TCR recognises the peptide and activates the T cell B27 receptor on APC and CD28 on T cell ligate, T cell is fully activated and proliferates - destroys cancer CTLA-4 is very similar to CD28 and also binds B27 and delivers inhibitory signal to shut T cell down - CTLA-4 antibodies block the inhibitory signal

Question 45

what is required for full activation of a T cell

Answer 45

ligation of the 2 receptors

Question 46

what is ipilimumab used for

Answer 46

metastatic malignant melanoma

Question 47

mode of treatment with dendritic cell vaccines

Answer 47

blood sample from patient culture dendritic cells in vitro w/ cytokines that promote APC function transfuse pts w/ APC after uptake of tumour antigen induces T cell responses to kill cancer

Question 48

adoptive cell transfer - tumour infiltrating T cells how is it done

Answer 48

excise tumour from pt plate out fragments of tumour cells and purify tumour cells and T cells from the tumour culture w/ IL-2 check they have specific tumour recognition then reinfuse back into the patient to kill the tumour cells

Question 49

what is CAR T cell therapy

Answer 49

CAR T cells are engineered to express antigen-targeted receptors specific for tumour antigens CAR includes an antigen binding domain fused to a transmembrane domain followed by T cell activation domains associated w/ TCR T cell modified w/ CAR now has new antigen specificity and binding its antigen supports T cell activation and killing of the target cell