immunotherapy Flashcards
what are the different immunosuppressive strategies
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
immunosuppression for allergy
anti-histamine to prevent allergic response
corticosteroids for severe allergy
anti-IgE, leukotriene antagonists to prevent bronchial constriction in asthma
what is a risk with blanket immunosuppression
opportunistic infections
why is cyclosporin so important in transplantation
major step forward in transplant survival
esp for cardiac transplant
why is T cell suppression important in transplants
by suppressing the T cell response you can prevent acute rejection
e.g. cyclosporin, rapamycin
how does cyclosporin work
calcineurin inhibitor
prevents IL-2 production by the T cell
how does rapamycin work
targets mTOR (mechanistic target)
targets IL-2 uptake by the T cell
what are the different types of immunty
how does natural active immunity work
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
how does passive immunity work
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
examples of passive immunity
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
immunoglobulin for post-exposure prophylaxis and what diseases are they given for
human normal immunoglobulin (HNIG):
- hep A
- measles
- polio
- rubella
specific immunoglobulins:
- hep B
- rabies
- tetanus
- VZV
what conditions is intravenous immunoglobulin used for
biologic therapy for 1y and 2y immune deficiencies and some AI disorders
what is IVIg
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
what is direct (targeted) immunotherapy
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
what is indirect immunotherapy
immune system is activated rendering it able to seek and destroy tumour cells
targets immune system
what are ADCs
antibody drug conjugates
examples of direct immunotherapy
monoclonal antibodies
chimeric antigen receptors (CARs)
Bi-specific antibodies
-
what do bi-specific antibodies do
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
examples of indirect immunotherapy
tumour vaccines
dendritic cell vaccines
adoptive cell transfer
cytokine therapies
checkpoint inhibitor therapies
stimulatory antibodies
what are dendritic cell vaccines
highly potent immune cells
can stimulate immune responses very effectively
combine tumour antigens w/ dendritic cells to drive T cell responses
what is adoptive cell transfer
cell transfer therapies where the cells have been trained to generate immune responses against the tumour antigens
what are cytokine therapies and what are they used for
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
what is a polyclonal response
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
how are monoclonal antibodies produced
immunisation
fusion and immortalisation of B cells
isolation and screening
expansion of desired hybridoma
what are car T cells
combination of antibody and T ell
used with multiple myeloma as a treatment
types of antibodies used in therapeutic monoclonal antibodies
human humanised - GE antibodies chimeric - mix of mouse and human fragment - part antibody, part extracellular receptor murine - mouse
what cancer is rituxan (rituximab) a first line treatment for
non-Hodgkins lymphoma
how does rituximab work
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
what other diseases can rituximab be used to treat
highly beneficial in RA and SLE
what type of therapy is infliximab
anti-TNF
what is infliximab used to treat
RA
ankylosing spondylitis
crohn’s disease
ulcerative colitis
how does infliximab work
chimeric antibody that blocks the function of tumour necrosis factor alpha
what is TNF and what does it stimulate
pro-inflammatory cytokine
stimulates an acute phase reaction
what is herceptin - trastuzumab - used for
treatment of HER2 +ve metastatic breast cancer (human epidermal growth factor receptor 2)
previously sufferers had a very poor prognosis
how does herceptin - trastuzumab work
antibody binds HER2 on cancer cells and marks them out for destruction by the immune system
what % of breast cancers are HER2+ve
15-20%
example of new anti-HER2 antibodies and how they work
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
what is Skyrizi - risankizumab - used to treat
plaque psoriasis
trials in crohn’s and psoriatic arthritis are ongoing
what is the target for risankizumab and what type of antibody is it
IL-23 p19 subunit
IgG1 humanised
how does risankizumab work
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
what are checkpoint inhibitor antibodies and what do they do
unlock the gateway to the adaptive immune system
powerful anti-tumour responses
potential for immune related adverse effects
example of anti-CTLA 4 antibody
ipilimumab
how do checkpoint inhibitor antibodies work
e.g. anti CTLA-4 antibodies
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
what is required for full activation of a T cell
ligation of the 2 receptors
what is ipilimumab used for
metastatic malignant melanoma
mode of treatment with dendritic cell vaccines
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
adoptive cell transfer - tumour infiltrating T cells
how is it done
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
what is CAR T cell therapy
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
