Cancer Flashcards
Targeted therapy
Better efficacy, less side effects
Target mutations, development of tumour, highly expressed/active protein, chromosome abnormality
TKIs
Tyrosine kinase inhibitors
Target the receptor or enzyme. Block activation off signalling pathway
Common side effects of targeted therapies
diarrhoea, liver problems, blood clotting, wound healing
Less nausea and fatigue overall
BCR-ABL translocation
Both express kinases
Chromic myeloid lukemia
exchange between 9 and 22 (Philadelphia chromosome)
Uncontrolled cell growth and impaired differentiation
Imatinib mesylate
Disappearance of Philadelphia chromosome (and GI cancer)
also targets c-KIT and PDGFR (growth factor))
Targeting lung cancer
EGFR - erlotinib (successful trial - PFS), gefitinib
ALK - aletinib
Antibodies
Fab - recognition (light and variable and epitope/CDR)
Fc - binding (constant)
Antibody therapy
Can be Fab only, protein Fc or engineered Fc (chimeric, humanised, human)
Conjugation to drugs, radioisotopes or nanoparticles
Creating antibodies
Immunise mice and isolate B cells and put in cancer (myeloma) cells. Screen for antibodies that bind to the cancer cells and harvest
Antibodies in cancer
Cause apoptotic pathway
Immune response
Block angiogenesis
Delivery of toxin
Types of antibody mediated cytotoxicity
ADCC - antibody-dependant cellular cytotoxicity
CDC - complimentary-dependant cytotoxicity (bind to C1q)
Effector cell recognises antibody -> phagocytosis or lysis
Breast cancer targets
ER and PR - hormones
HER2/ErbB2 - epidermal growth factor receptor
EGFR - triple negative
Trastuzumab/Herceptin
HER2+ breast cancer
Humanised antibody causes ADCC and CDC and stops dimerisation
Can have fatal infusion reactions + cardiomyopathy and pulmonary toxicity
Herceptin vs antracyclines/chemo
increased overall survival by 5 months
Better in combo with chemo than chemo alone
Herceptin resistance
Increase in PI3K/AKT activation
Can use mTOR inhibitors to restore sensitivity
Cancer hallmarks
Sustained proliferation signalling, evade growth suppressors, replicative immortality, invasion/metastasis, induce angiogenesis, resist cell death, disregulate cellular energies, genome instability/mutation, autoimmune destruction, suppress immune responses
Tumour microenvironment
cancer, endothelial, immune cells, pericytes (line blood vessels), ECM (fibroblasts and red blood cells)
Hypoxic
no blood vessels
Tumours -> cytokines and GFs cause angiogenesis and ECM production
Angiogenesis
VEGFs activated endothelial cells, expression of cytokines cause hypersprouting of tip/stalk cells,
Chaotic vascular - blood vessels dilated, disorganised, high permeability
Prevent immune cell chemotaxis and extravasation
Anti-angiogenesis
Stop signal for blood vessels
VEGF-A inhibitors (regulates permeability and cell migration
Normalise vasculature and increase drug perfusion
(resistance possible - reversible if breaks taken)
Anti-angiogenesis drugs
Bevacizummab, aflibercept, ramucirumab
Side effects = bleeding/haemorrhage, hypertension, loss of protein/neutrophils, healing complications
Bevacizumab
Anti-angiogenesis
Combo with chemo = increase survival
No effect on OS (transient)
Reduce tumour volume, less corticosteroids needed (reduced edema)
Importance of VEGF-A
Expressed differently in tumours = measure serum/tumour levels first
More VEGF with progression of cancer
Extracellular matrix on angiogenesis
Reduce nutrient and oxygen supply, increase hypoxia, metabolic stress
Blocks angiogenesis inhibitors
Cytokines/GFs in TME
Alter myeloid cell differentiation (macrophages and dendritic cells w/o antigen presentation), suppress T cell effectors, decrease MHC I presentation, stop targeting self via immune check-points
Tumour macrophages
M2 phenotype increased immune suppression, ECM production and angiogenesis
Causes of MHC I down regulation
Mutations, methylation, ncRNA, cell signalling altered, degraded in ER, blocked binding
Key immune check points
Priming
MHC=TCR and B7=CD28
B7=CTLA4 blocks immune response
Effector
PD1=PDL1 blocks immune response
Immune checkpoint inhibitors
CTLA-4 inhibitors (CD28 can be activated), ipilimumab
PD-1/PD-L1 inhibition, nivolumab (PD-1), atezolizumab (PD-L1)
Showed an increased in OS and PFS, quick + prolonged response
ICI non-responders
Tumour doesn’t have checkpoint, don’t display antigens to activate T cells, T cells don’t like the TME
Thus tumours with more mutations have a better response
ICI combination therapy
Combination better
Chemo and antiangiogenic (T cells can access)
Have greater adverse events (autoimmune - skin rashes, colitis, endocrinopathy) - don’t give if have autoimmune disorder
CTLA-4 less tolerated
T cell therapies
Use own immune cells or generic and isolate, expand, administrate
The T cells already within the body that can recognise cancer
Tumour infiltration lymphocytes
Walled underneath tumour and suppressive cytokine environment (checkpoints and co-stimulation)
Tumour infiltration lymphocyte therapy
Mixed population of T helper and cytotoxic cells
Administer with IL-2 after lymphodepletion to avoid immune response
Overall response 35%, sustained response, some complete responders, no relapses
T cell culture methods
Young - short period for numbers, 9% complete response
Conventional - one round, exposure, expand IFN-y producing cells, 14% complete response (difficult, long time period, expensive, transportation)
Engineered T cells
Genetic modification of naive lymphocytes to recognise tumour antigens
CAR - chimeric antigen receptor
Less success in solid tumours
CARs
extracellular antigen binding domain, transmembrane domain, intracellular activation domain (CD3 + costimulator - not environmentally dependant)
T cell specificity
CD-19 and 20, HER2, PSMA (prostate)
Hetrogenicity in the tumour limits choices
Find markers in genetic sequence (costly and slow)
Engineered T cell adverse responses
Cytokine release syndrome = super activation of T cells, oedema
neurological symptoms
Can use antinflamatory drugs dexamethasone and tocilizumab
CAR-T cell drugs
Axicabtagene ciloleucel
Ciltacabtagene autoleucel (patient derived)
Allogenic
Universal T cells (foreign)
Frozen and readily available
Low cost, simple, good quality
T cell therapy challenges
Heterogenecity of antigens
can’t access TME
When cytokines suppressing may exhaust CAR-T cells (stop being made)
CAR-T combination therapy
Anti-angiogenic - increase survival
CPIs - better overall response
Microbiome
Collection of microbes and genomic content - bacteria, viruses, fungi, etc.
Can sequence DNA/RNA -> microbe
Impacted by birth, genetics, diet, age, meds, toxins, stress, activity
Microbiome in cancer
20% of cancers caused by microbiome (Hep B, human papilloma virus, helicobactar pylori)
May create metabolites -> blood stream
Microbiome antitumour
Apoptosis activation, immune response, histone deacetylases inhibition
Inflammation and cytokine production from metabolites 0> Tregs and suppressor cells
Microbiome and immunotherapies
ICIs - different bacteria have different responses
Faecalibacterium = more immune cells, lymphoid and myeloid and MHC II
Microbiome transplant
Find who is a responder vs no responder based on microbiome (causative data?)
Transfer microbiome of responder into non-responder
Clinical responses observed
Some severe toxicities
Mesenchymal stem cells
Daughter cells differentiate, found in all tissues, migrate around body
MSC identification
Surface markers - CD73, CD90, CD105
spindle shape
MSC wound healing
Express integrins, adhesion molecules, chemokines
Reduce inflammatory response, no immune reaction
Cancer = non healing wound
MSC therapy for cancer
homing, immune modulation, delivery of chemotherapy or therapeutic proteins
Autologous
From the patient
MSC adverse effects
Autoimmune due to changes from plastic/culturing environment
Tumours might develop, blood clotting
Prochymal (remestemcel-L)
Allogenic from bone marrow
Approved in NZ 2012-2016, very small difference vs placebo
Acute graft vs host disease = reaction to donor T cells (corticosteroids don’t work)
Cartisten
Gel matrix structure for growth
Used for arthritis
Nausea and vomiting
CINV - chemo induced
Acute - within 24 hours
Delayed - after 24 hours
Anticipatory - learned response
reduced QOL of patients by 60% - economical and clinical
Cisplatin in particular
Emesis
Reflex response in the brain - vomiting centre in the medullary region of brainstem
Serotonin and dopamine receptors among others
Free radical cellular damage caused the release of serotonin from enterochromaffin cells in GI tract via 5TH3 receptors on vagal afferents
CINV therapy
Dexamethasone, ondansetron or domperidone
prior, during or after chemo
Serotonin and dopamine antagonists (lorazepam, halooperidol)
Critical in the first cycle as it is more likely to occur again
Ondansetron
5-HT3 antagonist
Least effective (8% vs placebo), better side effects (constipation and headache)
Before chemo, additive to opioid
IV (8.32 mg) or oral (16-32 mg), short half life 6 hours
Domperidone
D2 antagonist, delayed phase CINV
Increase risk of QT prolongation, arrhythmia, cardiac death, extrapyramidal symptoms
CYP3A4 inhibitors will increase risk
Dexamethasone
Corticosteroid, most effective
83% complete lack of vomiting at 20 mg
Don’t know MoA
Can use in combo with ondansetron
Aprepitant
NK1 R antagonist (substance P)
block 20% of emesis
Only used in high risk regimens, fatigue adverse effect, drug interactions CYPs
Combination with other anti-emetics
Cachexia
Wasting syndrome = severe loss of body weight (muscle and fat)
Inflammatory cytokines - consume aas, insulin resistance - can’t build muscles/protein
Decrease QoL, strength, increase fatigue, anorexia, hypermetabolism
Side effect of both chemo and cancer (particularly pancreatic/gastric plus colon/prostate)
Cachexia treatment
Magestrol acetate and corticosteroids
Progesterol improves appetite
exercise, high calorie food, nutritional counselling
Magesterol acetate
Increases appetite
Small effect on weight, no effect QoL
Clotting risks, adverse events, no change in death
low quality evidence
Corticosteroids
Advanced cancer - refractory
No effect on survival
Improve appetite and strength
