Immunotherapy and cancer I Flashcards
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
therapeutic use of HSP in cancer
- isolated the proteins from many different tumors. From range of different immunogeneicties
- all proteins identified were members of hsp70 and 90 families
- HSP derived from tumor lines is protective whereas HSP derived from normal tissue isnt
therapeutic use of HSP-peptide complexes
- HSP is increased in tumor tissue
- at present; 150 centres looking at the therapeutic use of HSP-peptides in cancer
- most non-randomised trials
- data so far is suggestive>definitive
antigenics related to HSP
- still no definitive results
- trials; at phase I/II/III in RCC; melanoma, colorectal, non-Hodgkin;s lymphoma, pancreatic; gastric; b-cell lymphoma
- all suggest some response
methods of tumor killing
- direct tumor cell killing
- immune mediated tumor cell killing
- vascular and stromal cell ablation
growth factor blocks; trastuzumab (herceptin)
targets ERBB2 (human epidermal growth factor) on breast cancer cells.
blocks ERBB2 signalling and allows targeting of ADCC
what is ADCC
antibody-dependent cell-mediated cytotoxicity
growth factor blockers; bevacizumab (avastin)
targets VEGF and block signalling.
Used against NSCLC, colon cancer, glioblastoma and kidney cancer
what therapies induce apoptosis?
- rituximab; anti CD20, used for CD20 positive Bcell non-hodgkin’s lymphoma and chronic lymphocytic lymphoma
- alemtuzumab (campath); anti CD25; used for B-CLL
immunomodulation
Ipilimumab (anti CTLA-4), blocks the inhibition due to CTLA-4 signalling.
used in metastatic melanoma.
Yttrium-labelled ibritumomab tiuxetan
antibody to CD20 delivering radiotherapy to follicular B-cell NHL
Brentuximab vedotin
antibody to CD30 delivering toxin to CD30+ B-cells in NHL
ontak
IL2 delivering diphtheria toxin in T cell lymphoma
new approaches; checkpoint inhibition
- blockade of effect cell death
- antibody against PD1
- expressed on T cells and can induce apoptosis when bound by PDL-1
- PDL-1 found oon timor cells
targetting inflammation
- can be both pro and anti tumrigenic
- Coley’s toxin ; acute inflammation though to be good, chronic inflammation isn’t
why is inflammation bad?
- regulation of the immune response
- Tregs induced which turn off response
- Myeloid derived suppressor cells / M2 cells
- Th2 switch
- NKT cells make IL13 which induces myeloid cells to produce TGFb
Th1 vs Th2
- Th1 response is good and will resolve tumor, Th2 isn’t and won’t.
- Aim of therapy is to resotre the Th1 response
