Immunotherapy and cancer I Flashcards
(40 cards)
why target the immune system?
Ehrlich stated that;
- early tumors never become apparent because they are destroyed by the immune system
examples of some immune modulators
- Coley’s toxins
- Cytokines
- Pattern recognition receptor agonists
- HSP
- Ab therapy
- Inflammation
what is Coley’s toxin?
a therapy developed after it was observed that some cancer patients experienced spontaneous remission after developing bacterial infections.
what does Coley’s toxin contain?
originally, streptococcus pyogenes and serratia marcesens ; heat killed and injected into cancer patients.
what is the idea behind Coley’s toxin?
immune system would be activated by the bacteria which would in turn attack the cancer cells
what is BCG?
bacillus calmette-guerin
- vaccine for TB
- good immunological adjuvant
- stimulaes the innate immune system
- used in bladded cancer
MOA of BCG
DC activation, direct NK activation, bystander T cell activation
Cytokines; interferons
- Type I interferon
- produced by virally infected cells
- viral detection pathways within most cells
- upregulates MHC class I, tumors antigens and adhesion molecules
- activates T-cells, B cells and DC
- used successfully in metastatic melanoma
- nasty flu like side effects
what does DC refer to?
dendritic cells; immune cells , APCs
interleukins
- T cell growth factor
- success in RCC and melanoma
- toxicity
- LAK cells, PBMC treated with IL2 and reinfused into patients
what is GM-CSF?
granulocyte macrophage colony stimulating factor
what is the function of GM-CSF?
cytokine that promotes myeloid cell development and maturation, and dendritic cell differentiation and survival in vitro
success rate of cytokine therapy
- interferons; 10-20%
- IL2; 10-20%
- IL2 + interferons; 40%
- GMCSF; ?
- GMCSF + IL2; 20%
pattern recognition
- intra and extra cellular sensors pathogens associated molecular patterns (PAMPs)
- conserved between species
4 families of pattern recognition
- Toll-like receptors
- Nucelotide-binding oligomerisation domain (NOD_-like receptors
- Retinoic acid inducible gene (RIG)- like receptors
- DNA sensors
pattern recognition receptors ; PRR
- originally though of as sensors for infection but more recently receptors for endogenous ligands
- Danger Associated Molecular Patterns (DAMPs)
- cell injury, stress or cell death
what are toll-like receptors?
- discovered in drosophila ; important in dorsoventral development but also in defence
- PR molecs. for bacterial and viral ligands
- stimulate cytokine relase
TLR signalling pathway
- recognise specific PAMPs present on pathogens.
- receptor activated
- adapter molecules recruited to TLR initiating signalling cascade
- downstream signalling cascade = activation of various TFs
- activated TFs translocate to nucleus and induce expression of pro-inflam. cytokines and chemokines.
- inflam. response
- TLR signalling downregulated to prevent excessive inflammation and maintain immune homeostasis
TLR in cancer therapy
- BCG used in adjuvants TLR2 and 4 mostly used in bladder cancer
- MPL, IPS, TLR4 agonist
- Stimuvex; MUC1 peptide and AS04 used in NSCLC
intracellular PRR
- Poly I;C, synthetic dsRNA. Direct effect on tumors causing cell death; induction of apoptosis
- activated in immune response
- used in glioma, prostate, breast, melanoma, ovarian
T cells and DCs
- induce death in a TC = correctly stimulate the DC which endocytoses it
- TC will release signals = activate/mature the DC
- correct presenation of the TC peptides by the DC to the adaptive response
what are HSPs?
heat shock proteins
- some HSP are stress inducible, others are constitutively expressed
- some HSP are upregulated by specific stress type, others by many stresses
HSP; effects on adaptive immune system
processing of peptide for presentation
HSP; effects on innate immune system
cytokine production and upregulation of co-stimulatory molecules
