14 - cancer immunotherapy Flashcards
effect of immunocompromised on cancer
increases your susceptibilty
role of Il-2 and cancer
immunoprotective against cancer
TIL
tumour infiltrating T-lymphocytes
increased numbers of Tumour Infiltrating T-lymphocytes
linked to increased chance of cancer survival
hyperploidy
too many chromosomes
often seen in cancer cells
calreticulin
CRP55 protein
binds to unfolded proteins from abnormal nucleus to prevent them from being replicated
activates MHC I complex
causes macrophages to be activated to engulf cancerous cells
naive T cells become effector T cells
3 stages of cancer immune surveillance
1 - elimination
2 - equilibrium
3 - escape
cancer immune surveillance
equilibrium
cancer cell recognition CD8 T cell expansion B cell activation NK cells and antibodies kill cells T reg cells monitor immune response death of some tumour cells
importance of equilibrium stage
cancerous tumour is contained by immune system but not completely destroyed
cancer tumour escape stage
tumour antigen editing via genomic instability
immune evasion
tumour no longer recognised by immune system
tumour microenvironment becomes immune suppressive
stage targeted by cancer immunotherpayh
tumour escape stage
impediments to anti-tumour therapy
- most tumour antigens are recognised as self antigens not as foreign
- chemotherapy is aggressive and destroys many healthy cells, depletes immune system
- tumour microenvironment suppresses immune system
immune suppressive signals of tumour microenvironment
increased no. of suppressive cytokines
decreased MHC I expression in tumour cells
infiltration of T reg cells –> inhibition of dendritic cells
co-stimulatory pairs important for
T cell activation
why do we need immunotherapy
radiotherapy and chemotherapy are potentially dangerous
advantages of cancer immunotherapy
more targeted and specific to cancer cells
more powerful (attacks cancer systemically)
universal (applies to all cancers)
has good memory (via T cells) –> durability of protection
increase in research into immunotherapy
after introduction of hybridoma technology and monoclonal antibody production
aim of immunotherapy
maximise immune activity and minimise immune suppressors
role of cancer vaccines
prime body against likelihood of having cancer
types of cancer vaccination
passive
- therapeutic monoclonal antibodies
active
- e.g. HPV vaccine
other methods of immunotherpay (3)
immune system modulators
e.g. IL-2 activates CD8 T cells
immune checkpoint modulation
(changes the way T cells interact with co-stimulatory pairs)
immune cell therapy
method of therapeutic monoclonal antibodies
carry cytotoxic agents to tumour
guides immune cells towards tumour
induce complement mediated lysis of tumour or ADCC
blocks activity of tumour-specific proteins with receptors
ultimately prevents division
types of therapeutic monoclonal antibodies
radioimmuno conjugates
immunocytokine
immunotoxin
immunoliposome
radioimmunoconjugate
antibody bound to radionuclide which provides energy to kill cancer cell
limitations of immunotoxins
antibody must have high affinity and specificity for toxin or cause cause damage as highly toxic
have to be targeted to cancer cell then effective
Bettsy Patterson
diagnosed with Non Hodgkins Lymphoma cancer
lots of chemotherapy treatment
lots of horrible side effects and no permanent effective cancer treatment –> NHL returns
first monoclonal antibody treatment approved for
cancer
Rituximab
Rituximab
chimeric human-mouse mAb targeted against CD20 on B cells
lyses CD20 via ADCC or human complement pathway
effect Of Rituximab on Bettsy
tumour decreases
nodes disappear
pain decreases
very few side effects
mutations in BCRA2 tumour suppressor gene
increased chance of breast or ovarian cancer
HER2
unique antigen expressed on surface of breast cancer cells
herceptin
humanised monoclonal antibody
blocks attachment of human epidermal growth factor to HER2
prevents growth and division of breast cancer cells
Sola
humanised monoclonal antibody (neuroprotector)
binds to amyloid B peptides
prevents build up of plaques in neurons causing alzheimers
Tocilizumab
humanised monoclonal antibody
treatment of rheumatoid arthritis
blocks binding of IL-6
no binding = no inflammation at joints
immune checkpoint modulation
prevent over-stimulation that could be damaging
strength of interaction determines how upregulated the T cell will be
use antibodies and agonists/antagonists
cancer therapy targets immune checkpoint inhibitors
mechanism of immune checkpoint protein inhibition
- co-stimulation via CD28 ligation –> transduction of T cell activation signals
- blockage of immune checkpoint protein (e.g. CTLA4) enhances T cell signalling
- “brakes” on immune system released
anti-CTLA4
antibodies can be used to prevent CLA4 binding to B7
therefore increases T cell activation and cancer cell killing
Theralizumab - TGN1412
investigational immunomodulatory drug for rheumatoid arthritis
binds to CD28 co-stim pair on T cells
potent agonist
stimulates anti-inflammatory cytokine production e.g. IL-10
clinical trials in humans
- dose too high
- cytokine storm caused
use of TILs in cancer therapy
able to target cancer cells
not enough within tumour to eradicate it or overcome immunosuppressive signals
attempts to introduce massive populations of activated TILs as treatment
method of TIL treatment
TILs are collected from samples of the tumor
TILs that show best recognition of the patient’s tumour in lab are selected
Cells are activated with cytokines and re-infused into the patient’s bloodstream
limitations of TIL treatment
expensive
time consuming
advantages of TIL treatment
can last for years
transgenic TILs
T cells are engineered to have a specific transgenic TCR which we know has high affinity to a certain tumour antigen
CAR-T cells
Chimeric Antigen Receptor Modified T Cells
a form of adoptive immune cell therapy
method of CAR-T cells
T cells collected from patient
T cells modified to express protein (chimeric antigen receptor)
Replace T cell receptor with antibody complex
Grow large populations in lab
CAR-T cells re-infused into patient
importance of CAR
modified form of the T cell receptor
binds to cancer cells
once bound, T cell becomes activated and kills cancer cell
does not rely on MHC
antibody-guided (molecular) imaging
radio-labelled antibodies used to located cancer cells by molecular imaging e.g. CT scans MRI PET
how does antibody-guided molecular imaging work
antibody carries radioligand to cancer cell
radio ligand bound decays when bound to cancer cell
decay releases neutrons and positrons
positrons bind to electrons and release photons
picked up by PET or CT imaging
2 most promising immunotherapy tools
immune checkpoint inhibitors and CAR-T T cells
