Immunology 6 Immunotherapy Flashcards
What is immunotherapy? :
- A therapy to control the immune system?
or
- Harnessing the power of the immune system to fight disease?
both
Used to be only top one e.g. supressing in transplants but now both
Immunosuppression is used when?
Used in allergy and autoimmune but also in transplant rejection as well
immunosuppresion - Blanket immune suppression (supressing immune system as whole) - what is the problem with this?
Opportunistic infections
Strong need to develop tailored therapies that target the specific immune response but leave the rest of the immune system free to fight disease
what is hyperacute rejection?
not as much of a problem these days, for some reason the immune system has seen these antigens before, matching these days through blood groups and tissue types stops this
what is acute rejection?
immune system recognising non-self antigens over period of 10-14 days, again not as much as a problem these days due to tissue matching
Acute rejection in particular is associated with T cell responses that mediate immune cell infiltration into the graft and effect its rejection
how do you inhibit T cells?
T cells control all other arms of the immune response
IL-2 is food for T cells, they produce it and take it up form the environment
If you supress them from producing IL-2 then you supress the T cell response very effectively and if you do that you prevent acute rejection of transplants
what are the different types of immunity?
what is the difference between passive and active immunity?
what are some exampels of passive immunity?
Snake or spider bites, scorpion or fish stings - passive infusion of antibody specific for the toxin
Hypogammaglobulinaemia – primary or secondary Infusion of g-globulins to reduce infection
Rabies Immunoglobulin -“Post-exposure prophylaxis” together with vaccination
Intravenous Immunoglobulin - what is it used for?
A biologic for primary and secondary Immune deficiencies
If your body doesn’t make antibodies then intravenous ig is a great therapy for you
What is IVIg?
- Plasma-derived IgG is a key biologic for replacement therapy in primary and secondary immunodeficiency disorders
- Also used for some autoimmune disorders
- Polyclonal IgG preparation usually given intravenously (IVIg) but can also be applied subcutaneously (SCIg)
- Very high dose - 1-3g/Kg
- Source – pooled from several thousand donors (1,000 – 100,000)
Need to make sure no virus in it, need to be a very pure prep
Replaces your antibody in your blood stream
Different types of immunotherapy:
what is directed 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
Target: The tumour
Different types of immunotherapy:
what is indirect immunotherapy?
The immune system is activated rendering it able to seek and destroy tumour cells
Target: The immune system
whata re some examples of direct immunotherapy?
Monoclonal antibodies
Chimeric antigen receptors (CARs)
Bi-specific antibodies
what are some examples of indirect immunotherapy?
Tumour vaccines
Dendritic cell vaccines
Adoptive cell transfer
Cytokine therapies
Checkpoint inhibitor therapies
Stimulatory antibodies
what are cytokine therapies?
Cytokine therapy has proven to be a novel therapeutic approach in treating patients with advanced malignancies. The purpose of this type of therapy is to manipulate the immune response in such a way as to generate the appropriate immune effector cells to eradicate solid tumors.
- Immunomodulatory cytokines to activate anti-tumour immunity
- Used in specific cancers
pegylated IFN-a, IL-2,
what are polyclonal antibodies?
Polyclonal response: Immunisation with 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 with different Variable regions bind multiple epitopes
what are monoclonal antibodies?
Isolate a single antibody producing clone. Single specificity and recognises one epitope and everyone of the antibodies made by the clone will be the same as another
A monoclonal antibody is an antibody made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies can have monovalent affinity, binding only to the same epitope.
Therapeutic Monoclonal Antibody Market: Approved Drugs by Product Type, 2020
what are the different types?
Murine – mouse monoclonal antibody
Fragment – part antibody and part cell receptor
Chimeric – antibodies which are now mainly human except the region that bind to the antigen which are mice, mix of mice and human
Main type now is human which are generated in mice, transgenic mice so when you immunise them they produce human antibodies and not mice
Humanized – engineered antibodies so that they are nearly 100% human
what is Rituxan (rituximab)?
- First line treatment for non-Hodgkin’s lymphoma
- Specific for the CD20 molecule on the cell surface of a small sub-population of B cells
- Crossover mAb - Originally developed for NHL and lymphoma but now found to have highly beneficial effects in rheumatoid arthritis and probably systemic lupus erythematosus (SLE)
Recruits in immune cells to kill it
what is Herceptin (Trastuzumab)?
- Approved in 1998 (USA) for treatment of human growth epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer - Previously HER2+ sufferers had a very poor prognosis
- The antibody binds HER2 on cancer cells and marks them out for destruction by the immune system
- 15-20% of breast cancer cases are HER2+
what are checkpoint inhibitors?
- Checkpoint inhibitor antibodies unlock the gateway to the adaptive immune system
- Powerful anti-tumour responses
- But potential for immune related adverse effects
Don’t care about the cancer, we are targeting the immune response so it can kill the cancer
Checkpoint inhibitor therapy is a form of cancer immunotherapy. The therapy targets immune checkpoints, key regulators of the immune system that when stimulated can dampen the immune response to an immunologic stimulus. Some cancers can protect themselves from attack by stimulating immune checkpoint targets. Checkpoint therapy can block inhibitory checkpoints, restoring immune system function.
Checkpoint immunotherapy:
what is show here?
On the left, antibodies bind to CTLA-4 preventing inhibition and allowing cells to become activated
Left – relationship between T cells and immune cells
Right – relationship for this antibody is between T cell and tumour cells, normally the tumour cells tricks the T cells into thinking everything is all okay. By blocking PD1 or PDL1 you remove the block and the T cell is fully activated
Anti-PD1/PD-L1 antibodies:
Disrupt immunoevasion by the cancer cell
Dc vaccines – mode of treatment
dendtritic cell vaccine - what is it?
- 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
what is ACT – tumour infiltrating T cells?
ACT = adoptive cell transfer
Excise tumour from patient, chop it up, plate up fragments of tumour and purify T cells frpm the tumour and culture with IL2 to grow lots of T cells and then reinfuse back into the patient
Adoptive cell transfer (ACT) is the transfer of cells into a patient. The cells may have originated from the patient or from another individual. The cells are most commonly derived from the immune system with the goal of improving immune functionality and characteristics.
what is CAR T cell therapy?
- CAR T cell 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 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
Immune therapies:
- Immune therapies can be used to _________ the immune response
- Can be immunosuppressive or immune ________ (more so now)
- Targeted __________ antibodies are changing modern medicine – one introduced each month
- The checkpoint inhibitors offer new options for treating a range of _______ – in >2,000 CT!
- Cellular immunotherapies are also very powerful:
- T cells
- Dendritic cells
- CAR-T cells
modulate
boosting
monoclonal
cancers
