Immunotherapy Flashcards
Immunosuppression
Used in allergy and autoimmune disease. Blanket immune suppression (suppress teh immune reponse). Risk of opportunistic infections.
Acute transplant rejection
Acute rejection in particular is associated with T cell responses that mediate immune cell infiltration into the graft and effect its rejection
Cyclosporin FK506
Inhibits phosphatase calcineurin. This dephosphorylates and activates the T-cell transcription factor NFATc,
Rapamycin
Inhibits mTOR
Passive Adaptive immuntiy
Placental transfer of IgG
Colostral transfer of IgA
Immunoglobulin therapy or immune cells
Advantages of passive immunity treatment
Gives immediate protection
A quick fix
Disadvantages of passive immune treatment
Short term effect – no immunological memory
Serum sickness – incoming antibody is recognised as a foreign antigen by the recipient and results in anaphylaxis
Graft versus host disease (cell grafts only) – incoming immune cells reject the recipient
Snake or spider bites, scorpion or fish bites
passive infusion of antibody specific for the toxin
Hypogammaglobinaemia
primary or secondary
Infusion of γ-globulins to reduce infection
Immunoglobulin for post-exposure prophylaxis
Human Normal Immunoglobulin (HNIG) Hepatitis A Measles Polio Rubella Specific Immunoglobulins Hepatitis B Rabies Tetanus Varicella-Zoster Virus
IV immunoglobulins
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)
Indications for IVIg
Primary immunodeficiency Wiskott Aldrich Syndrome IgG subclass deficiency with recurrent infections Kawasaki disease ITP
Direct 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
Indirect Immunotherapy
The immune system is activated rendering it able to seek and destroy tumour cells
Direct Immunotherapy examples
Monoclonal antibodies
Chimeric antigen receptors
(CARs)
Bi-specific antibodies
Indirect Immunotherapy examples
Tumour vaccines
Dendritic cell vaccines
Adoptive cell transfer
Cytokine therapies
Checkpoint inhibitor therapies
Stimulatory antibodies
Cytokine therapy
Immunomodulatory cytokines to activate anti-tumour immunity
Usually pegylated
IFN-alpha
Cytokine therapy used in the treatment of melanoma
IL-2
Cytokine therapy used in kidney cancer
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
Therapeutic Monoclonal Antobodies
Murine
Chimeric
Humanized
Rituxan (Rituximab)
Monoclonal antibody specific for the CD20 molecule on the cell surface of a small sub-population of B cells. It is the first line treatment for non-hodgkins lymphoma. Also useful in rheumatoid arthritis.
How does rituximab work
Recruits proinflammatory cells or activates the complement system killing the cell.
Infliximab (anti-TNF alpha)
Used in ankylosing spondylitis, crohns, UC.
It blocks the function of tumour necrosis factor alpha (TNF-alpha)
Herceptin (Trastuzumab)
The antibody binds HER2 on cancer cells and marks them out for destruction by the immune system
Treatment of human growth epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer
Previously HER2+ sufferers had a very poor prognosis
Pertuzumab
Binds both HER2 and prevents dimerisation with HER3 receptor which adds another benefit to antibody therapy
Check point inhibitors
Checkpoint inhibitor antibodies unlock the gateway to the adaptive immune system
Powerful anti-tumour response through immense activation of T cell
Potential for immune related adverse effects
Anti-CTLA-4 antibodies (ipilimumab)
Dendritic cell are able to activate the T cell (best capable) via CD28 receptor. CTLA-4 ligand will shut it down. Outcompetes CD28. Ipilumimab blocks the relationship between CTLA4 and the T cell therefore allowing it to be fully activated.
Anti-PD1/PD-L1 antibodies (Pembrolizumab)
PD-1 receptor ligand between the tumour cell and the t cell. This results in suppression of the T cell. By inhibiting PD-1 or the PD-1 ligand, the T cell will not be able to be suppressed.
Dendritic Cell Vaccines
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
Chimeric Antigen Receptor T cells
Combine antibody and T cell response to improve immunity
Increases longevity & overcomes T cell tolerance mechanisms
Need to identify a tumour restricted antigen
Tumour escape if antigen no longer expressed
mainly used in lymphoma
