Immunotherapy Flashcards
types of immunosuppression
General immunosuppressive strategies • Allergy and autoimmune disease • Blanket immune suppression • 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
with a diagram describe the methods for inhibiting t cell activation to treat graft rejection
see notes
active adaptive immunity
infection/exposure
immunisation vaccines
passive adaptive immunity
placental transfer of IgG
colostral transfer of IgA
IG therapy or immune cells
examples 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 IG - PEP together with caccination
examples of immunoglobulin for PEP
Human Normal Immunoglobulin (HNIG) Hepatitis A Measles Polio Rubella
Specific Immunoglobulins Hepatitis B Rabies Tetanus Varicella-Zoster Virus
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)
licensed indications for IVIg
Primary immunodeficiency
Wiskott Aldrich syndrome
IgG subclass deficiencies with recurrent infections
Idiopathic Thrombocytopenic Purpura
Kawasaki disease
Common variable immunodeficiency
Multiple myeloma/CLL
Children with HIV
Guillain-Barre syndrome
Allogenic bone marrow transplantation—prevention of graft
versus host disease (GVHD) and infections
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
target for direct immunotherapy
the tumour
indirect immunotherapy
the immune system is activated rendering it able to seek and destroy tumour cells
target for indirect immunotherapy
immune system
examples of direct immunotherapy
Monoclonal antibodies
Chimeric antigen receptors (CARs)
Bi-specific antibodies
examples of indirect immunotherapy
Tumour vaccines Dendritic cell vaccines Adoptive cell transfer Cytokine therapies Checkpoint inhibitor therapies Stimulatory antibodies
describe cytokine therapies
- Immunomodulatory cytokines to activate anti tumour immunity
- pegylated IFN-a, IL-2, GM-CSF
- Used in specific cancers
- Pegylated is an effective anti-viral IFN-a therapy and used in melanoma
polyclonal vs monoclonal 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
Typical antibody response: in humans pathogenic insult, vaccines etc. - polyclonal
Antibodies with different Variable regions bind multiple epitopes
making monoclonal antibodies
immunisation
fusion + immortalisation of B cells
isolation and screening
expansion of desired hybridoma
discuss 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)
with a diagram show how rituximab works
see notes
discuss infliximab (anti-TNF therapy)
• First approved November 1999 for the treatment
of rheumatoid arthritis
• Now used to treat several other AI diseases
– Ankylosing spondylitis
– Crohn’s disease
– Ulcerative colitis
• Chimeric antibody that blocks the function of
tumour necrosis factor alpha (TNF)
– TNF is a pro-inflammatory cytokine that stimulates
an acute phase reaction
discuss 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+
how does pertuzumab differ from trastuzumab
directed at the dimerisation domain of HER2 - disruption of dimer formation
discuss checkpoint inhibitors
Checkpoint inhibitor antibodies unlock the gateway to the adaptive immune system
• Powerful anti-tumour responses
• But potential for immune related adverse effects
discuss 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.
