Immunotherapy and cancer Flashcards
1
Q
What are some immune modulators?
A
- Coley’s toxins
- cytokines
- pattern recognition receptor agonists
- HSP
- ab therapy
- inflammation
2
Q
What are coleys toxins?
A
- strep pyogenes and serratia marcesens
- unsure of mechanism of action
- potentially TNF, streptokinase or PAMPs
3
Q
What is BCG?
A
- bacillus calmette-guerin
- vaccine for TB
- good immunological adjuvant
- stimulates the innate immune system TLRs
- used in bladder cancer
- mechanism of action - DC activation, NK activation
4
Q
Describe the cytokine : interferon
A
- type 1 interferon (a and b)
- produced by virally infected cells
- viral detection pathways within most cells
- upregulates MHC class I, tumour antigens and adhesion molecules
- activates T cells and B cells and DC
- used in metastatic melanoma
- bad side effects
5
Q
Describe the cytokine: interleukin 2
A
- t cell growth factor
- success in RCC and melanoma
- toxicity
- LAK cells, PBMC treated with IL-2 and re-infused into patients
6
Q
Describe the cytokine: GM-CSF
A
- stimulates APC
- trialled in melanoma
- may benefit in conjunction with IL-2
- others: IL-4, IL-1. IL-7
7
Q
What is the success rate of cytokine therapy?
A
- interferons - 10-20%
- IL-2 - 10-20%
- IL-2+interferons - 40%
- GM-CSF+IL-2 - 20%
8
Q
What is pattern recognition?
A
- intra and extra cellular sensors - pathogen associated molecular patterns (PAMPs)
- conserved between species
- 4 families :
- toll-like receptors
- nucleotide-binding oligomerisation domain (NOD) like receptors
- retinoic acid inducible gene (RIG) like receptors
- DNA sensors
9
Q
Describe PRRs
A
- originally thought of as sensors for infection - but more recently receptors for endogenous ligands
- Danger associates molecular patterns (DAMPs_
- recognise cell injury, stress or cell death
- eg. HSP, HMGB1
10
Q
What are toll-like receptors?
A
- pattern recognition molecules for bacterial and viral ligands
- most mammalian sp : 10-15
- stimulate cytokine release
- amplify the immune response
11
Q
Describe TLRs in cancer therapy
A
- BCG (TICE) used as adjuvants TLR2 and 4 - mostly used in bladder cancer
- MPLA (monophosphoryl lipid A), lps, TLR4 agonist
- stimuvex - MUCI peptide and AS04 used in NSCLC
- detox - MPLA and myco cell wall used with peptide vaccines in metastatic cancer
12
Q
Describe intracellular PRRs
A
- poly I: C synthetic dsRNA, direct effect on tumour causing cell death - induction of apoptosis
- also activated the immune response
- used in glioma, prostate, breast and melanoma
13
Q
What are heat shock proteins HSP?
A
- some HSP are stress inducible, others are consitutively expressed
- some HSP are upregulates by a specific stress type, others by many types of stress
14
Q
What are heat shock proteins HSP?
A
- some HSP are stress inducible, others are constitutively expressed
- some HSP are upregulates by a specific stress type, others by many types of stress
- effects the adaptive immune system - processing of peptide for presentation
- innate immune system - cytokine production and upregulation of co-stimulatory molecules
15
Q
Describe the therapeutic uses of HSP in cancer
A
- HSP is increased in tumour tissue
- at present there are - 150 centres looking at therapeutic uses
- most randomised trials
- data = suggestive
16
Q
What are the major approaches of therapeutic antibodies?
A
- direct anti-tumoural ie blockade of growth signals and induction of apoptosis
- immunomodulation
delivery system
17
Q
How are growth factors blocked?
A
- trastuzmub (herceptin) - targets ERBB2 on breast cancer cells - blocks ERBB2 signalling and allows targeting of ADCC
- bevacizumbab (avastin) targets VEGF and blocks signalling, used in colon cancer
18
Q
How is apoptosis induced?
A
- rituximab - anti-CD20, used for CD20 positive B cell Non-hodgkins lymphoma and CLL
- alemtuzumsb (campath) - anti CD52, used for B-CLL
19
Q
What are some antibodies used in immunomodulation?
A
- ipilimumab (anti- CTLA-4) blocks the inhibition due to CTLA-4 signalling = used in metastatic melanoma
20
Q
How can different delivery methods be used for antibody therapy?
A
- yttrium-labelled ibritumomab tioxetan ab to CD20 delivering radiotherapy to follicular b-cell NHL
- brentuximab vedotin - ab to CD30 delivering toxin to CD30 + b cells in BHL
21
Q
Describe checkpoint inhibition
A
- blockade of effector cell death
- ab against PD-1 (programmed cell death protein 1)
- expressed on T cells and can induce apoptosis when bound to PDL-1
- PDL-1 can be found on tumour cells
- nivolumab and pembrolizumab
- combination therapy with ipilimumab
22
Q
Why is inflammtion bad?
A
- regulation of the immune response
- tregs induced which turn off response
- myeloid derived suppressor cells/M2 cells
- Th2 switch
- NKT cells make IL-13 which induce myeloid cells to produce TGF-beta
- Th1 response is good = resolve tumour
- Th2 will not
