Immunotherapy Flashcards
What are different kinds of immunotherapies?
- Immune suppressive therapies
- General suppression
- Transplant rejection
- Passive infusion
- Cytokine therapies
- Directed antibody therapy
- Monoclonal vs polyclonal
- Checkpoint inhibitors
- Cellular immunotherapy
- T cells
- Dendritic cells
- CAR-T cells
What does ‘blanket’ immune suppresion mean?
‘Blanket’ immune suppression means suppressing the entire immune system, risk of opportunistic infections:
- Need to develop tailored therapies that target specific part of immune system
What is the main risk of ‘blanket’ immune suppresion?
Opportunistic infections
Acute rejection is associated with what?
Acute rejection is associated with T cell responses that mediate immune cell infiltration into graft:
- Anti-rejection drugs massively increased graft survivability
How can T cell activation be inhibited?
Methods for inhibiting T cell activation to treat graft rejection, done by stopping them from producing IL-2:
- Cyclosporin
- Mechanism – targets calcinerin, effecting IL-2 production
- Rapamycin
- Mechanism - targets mTOR, affecting IL-2 uptake by T-cell
- Antibody treatment
- Mechanism - targeting costimulation
What are some drugs that inhibit T cell activation?
- Cyclosporin
- Mechanism – targets calcinerin, effecting IL-2 production
- Rapamycin
- Mechanism - targets mTOR, affecting IL-2 uptake by T-cell
- Antibody treatment
- Mechanism - targeting costimulation
Describe the mechanism of Cyclosporin?
- Mechanism – targets calcinerin, affecting IL-2 production
Describe the mechanism of:
- cyclosporin
- rapamycin
- antibody treatment
- Cyclosporin
- Mechanism – targets calcinerin, affecting IL-2 production
- Rapamycin
- Mechanism - targets mTOR, affecting IL-2 uptake by T-cell
- Antibody treatment
- Mechanism - targeting costimulation
What are the different types of immunity?
Contrast active and passive immunity?
- Active immunity
- Person infected or vaccinated with microbe
- Few days or weeks later individual makes potent adaptive immune response with T cells and antibodies
- Recovers from challenge with specificity and memory
- Passive immunity
- Serum given to patient (from immune individual)
- Infection and recovery with immunity
- Specificity but no memory
For active and passive immunity do they have:
- specificity
- memory
What are examples of passive immunity?
- Snake or spider bites, scorpion or fish stings
- Passive infusion of antibody specific for toxin
- Hypogammaglobulinaemia
- Primary or secondary infusion of IgG to reduce infection
- Rabies immunoglobulin
- Post-exposure prophylaxis together with vaccination
What are examples of things immunoglobulins for post-exposure prophylaxis can be used?
- Human normal immunoglobulin (HNIG)
- Hepatitis A
- Measles
- Polio
- Rebella
- Specific immunoglobulins
- Hepatitis B
- Rabies
- Tetanus
- Varicella-zoster virus
What is IV immunoglobulin?
A biologic for primary and secondary immune deficiencies:
- Plasma derived IgG used for replacement therapy
What are indications for IV immunoglobulin?
- Some autoimmune disorders
- Primary and secondary immunodeficiency’s
What are the different types of immunotherapy?
- Direct (targeted)
- Antibodies detect an antigen on tumour and destroy target by recruiting immune cells or delivering a toxin or radioisotope to it
- Target is the tumour
- Indirect
- Immune system activated, allowing it to seek and destroy tumour cells
- Target is the immune system
What is direct (targeted) immunotherapy?
- Antibodies detect an antigen on tumour and destroy target by recruiting immune cells or delivering a toxin or radioisotope to it
- Target is the tumour
What is indirect immunotherapy?
- Immune system activated, allowing it to seek and destroy tumour cells
- Target is the immune system
What are examples of direct and indirect immunotherapy?
- Direct
- Monoclonal antibodies
- Chimeric antigen receptors (CAR-T cells)
- Bi-specific antibodies
- Indirect
- Tumour vaccines
- Dendritic cell vaccines
- Adoptive cell transfer
- Cytokine therapies
- Checkpoint inhibitor therapies
- Stimulatory antibodies
For cytokine therapy:
- drugs
- effect
- indication
Drugs:
- Pegylated IFN-a
- IL-2
- GM-CSF
Effect:
- Immunomodulatory cytokines to activate anti-tumour immunity
Indications:
- Specific cancers
What is the difference between polyclonal and monoclonal antibodies?
Immunisation with antigen will typically lead to polyclonal response:
- Many different B cell clones generate antibodies specific for the antigen
- But a number of epitopes will be bound by antibodies
- Antibodies with different variable regions bind multiple epitopes
Monoclonal immune response is where a single antibody producing clone produces antibodies:
- Recognise only one epitope
What are different product types of therapeutic antibodies?
- Human (most common)
- Humanised
- Chimeric
- Mixture of mouse and human
- Fragment
- Murine
What are examples of therapeutic antibodies?
-
Rituxan (rituximab)
- Indication – originally developed for NHL and lymphoma, now found to benefit rheumatoid arthritis
- Mechanism – specific for the CD20 molecule on cell surface of small population of B cells, allowing immune system to kill it such as macrophages, compliment system and NK cells
-
Infliximab
- Effect – anti-TNF therapy
- Mechanism – chimeric antibody blocks function of tumour necrosis factor alpha (TNF), which is a pro-inflammatory cytokine that stimulates an acute phase reaction
- Indications – rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis
-
Herceptin, also called trastuzumab
- Mechanism – antibody binds HER2 on cancer cells and marks them for destruction by immune system
- Indication – HER2 positive metastatic breast cancer
-
Risankizumab
- Mechanism – targets cytokine associated with inflammatory response underlying plaque psorisasis
- Indication – plaque psoriasis
For rituxan (rituximab):
- indication
- mechanism
- Indication – originally developed for NHL and lymphoma, now found to benefit rheumatoid arthritis
- Mechanism – specific for the CD20 molecule on cell surface of small population of B cells, allowing immune system to kill it such as macrophages, compliment system and NK cells
For infliximab:
- effect
- mechanism
- indications
- Effect – anti-TNF therapy
- Mechanism – chimeric antibody blocks function of tumour necrosis factor alpha (TNF), which is a pro-inflammatory cytokine that stimulates an acute phase reaction
- Indications – rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis
For herceptin:
- mechanism
- indication
For risankizumab:
- mechanism
- indication
What is the effect of checkpoint inhibitors?
- Antibodies that unlocks the adaptive immune response so it can kill the cancer
What are the 2 types of checkpoint inhibitors?
- Anti-CTLA4 antibodies
- Mechanism - normally dendritic cell presents antigen from target cell with MHC, TCR on T cell binds to this and activates T cell. But the B7 part of the dendritic cell also needs to bind with CD28 of T cell for full activation, if B7 binds with CTLA-4 this causes inhibitor effect
- Anti-PD-1/PD-L1
- Mechanism - Tumour expresses high levels of PD-L1 which binds to PD-1 on T cell, inhibiting it and tricking it. This blocks this from happening
Describe the mechanism of anti-CTLA4 antibodies?
- Mechanism - normally dendritic cell presents antigen from target cell with MHC, TCR on T cell binds to this and activates T cell. But the B7 part of the dendritic cell also needs to bind with CD28 of T cell for full activation, if B7 binds with CTLA-4 this causes inhibitor effect
Describe the mechanism of anti-PD-1/PD-L1 antibodies?
- Mechanism - Tumour expresses high levels of PD-L1 which binds to PD-1 on T cell, inhibiting it and tricking it. This blocks this from happening
Describe the process of dendritic cell vaccines?
- Take blood sample from patient
- Culture cells in vitro
- With cytokines promote APC function
- Transfuse patients with APC after uptake of tumour antigen
What does ACT stand for?
Adoptive cell transfer
Describe the process of ACT?
- Take tumour cells from patient
- Assay for specific tumour recognition
- Select and expand to billions of cells
- Reinfuse post lymphodepletion
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 with the T-cell receptor
- T cell modified with CAR is endowed with a new antigen specificity, supporting T cell activation and killing target cell
What does CAR stand for?
Chimeric antigen receptors
How many generations of CAR are there, and what does each generation add?
- 1st generation
- 2nd generation
- 3rd generation
