CANCER IMMUNOTHERAPY P1 Flashcards
cancer associated antigens
- neoantigens
- overexpresssed self antigens
- self antigens that are expressed during embryonic development by are not expressed or are expressed at low levels after birth
neoantigens
result from gene mutations in cancer cells and have not been seen previously by the immune system
how can antigens on tumours initiate an immune response
cancer-associated antigens mark cancer cells as abnormal or foreign and can cause killer T cells to mount an attack against them
cancer cell strategies to evade detection by the immune system
- many cancer associated antigens are only slightly altered versions of self antigens and difficult for the immune system to recognise
- cancer cells may undergo genetic changes that may lead to the loss of the processing or presentation of cancer-associated antigens
- over expression of proteins (PDL1) which suppress immune response
- some cancer cells produce and secrete immunosuppressive cytokines (e.g. IL-10, TGF-beta)
tumour associated macrophages (TAM)
- tumours release a range of chemokines, cytokines and growth factors to attract monocyte into the tumour stroma where they differentiate into tumour associated macrophages (TAM)
- TAMs stimulate tumour growth, invasion, migration and metastatic spread
classical immunotherapy
the treatment of disease by inducing, enhancing or modulating an immune response
cancer immunotherapy
- antibody-based therapy
- vaccines
cell based therapies> - dendritic cells
- T cells
antibodies in cancer immunotherapy
exploits the expression of a specific antigen expressed by cancer cells but absent or expressed at low levels by normal cells
- to stimulate the host immune response to kill cancer cells
- to inhibit tumour growth signals
- to carry drug or a radioactive molecules to the cancer cells
rituximab (Rituxan)
- chimeric (mouse and human) monoclonal antibody against CD20 expressed on B-lymphocytes
- tumour cells can lose CD20 from their surface following treatment, resulting in CD20-negative tumour cells that are resistant to rituximab
rituximab indication
non-Hodgkin’s lymphoma
chronic lymphocytic leukaemia (CLL)
cancers which develops in B lymphocytes
side effects of rituximab
which can cause death and disability include:
- immune toxicity (depletion of B cells)
- CD20 is also expressed on normal B cells
- any healthy B cells destroyed by CD-20 targeted therapy can be readily replenished
- pulmonary toxicity
rituximab mechanism of action
cells death induced by:
- apoptosis
- ADCC antibody-dependent cellular cytotoxicity
- Fc arm of the antibody engages Fc receptor triggering (FcR)-positive inflammatory cells, such as natural killer cells and macrophages
- CMC complement mediated cytotoxicity
main side effect of herceptin
cardiac dysfunction
HER2
activates MAPK and PI3K pathways which increases cell growth, survival, adhesion, migration, and differentiation
Herceptin receptor
Herceptin binds to HER2 receptor
herceptin in HER2-overexpressing metastatic breast cancer
- in combination with paclitaxel for first-line treatment
- single agent in patients who have received one or more chemo regime
administration of herceptin
IV infusion
SC injection - early breast cancer only
breast cancer every 1 or 3 weeks up to 1 year
gastric cancer every 3 weeks
immune checkpoint proteins
- can suppress T-cell response
- inhibitory check point inhibitors are crucial for modulating the duration and amplitude of physiological immune responses in peripheral tissues
- minimise collateral tissue damage
CTLA-4
cytotoxic T-lymphocyte-associated protein 4-receptor
inhibitory checkpoint receptor protein expressed on T cells
Ipilimumab
- antibody against CTLA-4 expressed on T cells
- ipilimumab blocks negative signalling from CTLA-4
process in which ipilimumab blocks CLTA-4
- antigen-presenting cell (DC or macrophages) presents a processed antigen in the context of MCHII
- recognised by TCR on T-cell
- for T-cell activation co-stimulatory signals from APC is needed (CD28 binds B7)
- CTLA-4 binds B7 no T-cell to terminate activation
- ipilimumab blocks CTLA-4
administration of ipilimumab
intravenous infusion 3mg/kg every 3 weeks for 4 doses
common side effects related to inflammatory responses
fatigue
diarrhoea
skin rash
vomiting
ipilimumab indication
- ipilimumab is approved for use in combination with the PD-1 inhibitor nivolumab to treat unresectable melanoma
- advanced treatment-naive renal cell carcinoma (RCC)
- metastatic microsatellite instability-high (MSI-h) or mismatch repair deficient (dMMR) colorectal cancer that has progressed on previous treatment
PD-1
checkpoint receptor protein expressed on T cells and B cells
PD-L1/PD-L2
- PD-L1 and PD-L2 are ligands to PD1 and is expressed by dendritic cells, macrophage (APC)
- PD-L1 is present in to cytoplasm and plasma membrane of cancer cells, but not all cancers or all cells within a cancer express PD-L1
which cancers is PD-L1 expressed
- especially in NSCLC
- melanoma
- renal cell carcinoma
- gastric cancer
- hepatocellular/cutaneous
- various leukaemias
- multiple myeloma
the cancer immunity cycle blocked by PD-L1/PD1
- tumour cells produce mutated antigens that are captured by dendritic cells
- the dendritic cells prime T cells with tumour antigen and stimulate the activation of cytotoxic T cell
- activated T cells then travel to the tumour and infiltrate the tumour environment
- the activated T cells recognize and bind to the cancer cells
- the bound effector T cells release cytotoxins, which induce apoptosis in their target cancer cell
- the cancer cell can block the T-cell attack through PD-L1 (cancer cells) binding to PD1 on T-cell
how do tumours use PD1-mediated immune suppression to avoid immune surveillance
- PD-1 binds to PD-L1/PD-L2 which inhibit T-cell proliferation
- some cancer cells have large amounts of PD-L1, which helps them evade immune attack
proinflammatory molecules that induce PD-L1 expression
types I and II IFN-y
TNF-a
LPS
GM-CSF
VEGF
cytokines IL-10 and IL-4
- the most potent inducer is IFN-y
- IFN-y and TNF-a are produced by activated type 1 T cells
regulation of PD-L1 expression by GM-CSF and VEGF
GM-CSF and VEGF are produced by a variety of cancer stromal cells, the tumour microenvironment upregulates PD-L1 expression, thereby, promotes immune suppression allowing tumour cells to escape immuno-surveillance
PD-1 inhibitors
PROGRAMMED CELL DEATH PROTEIN 1
pembrolizumab
Nivolumab
PDL-1
PROGRAMMED DEATH-LIGAND 1
atezolizumab
avelumab
durmalumab
microsatellite instability and mismatch DNA repair
- microsatellite is a set of short repeated DNA sequences in which certain DNA motifs (ranging in length from 1-6 or more base pairs) are repeated, typically 5-50 times
- microsatellite instability results from impaired DNA mismatch pair
-MMR corrects DNA errors that spontaneously occur during DNA replication (single base mismatches, short insertion or deletion) - prevent mutations
cause of defects in MMR
defects in MMR are associated with genome-wide instability and increased TMB
Pembrolizumab
approved for adults and paediatric pts with unresectable or metastatic solid tumours that have been identified as having a biomarker referred to as a microsatellite
instability-high (MSI-H) or mismatch repair deficit (dMMR)
side effects of checkpoint inhibitors
diarrhoea
pneumonitis
rashes and itchiness
problems with some hormone levels
kidney infections
administration of checkpoint inhibitors
- intravenous infusion every 3 weeks until disease progression or up to 24 months in patients without disease progression
- atezolizumab (PD-L1) available as subcutaneous injection, cuts treatment time from to 7 min from about 30-60 for an infusion
chimeric antigen receptors T-cell therapy (CAR-T)
- T-cells are modified to express CARs
- CARs are genetically engineered receptors that combine the specific binding domains from a tumour targeting antibody with T-cell signalling domains to allow specifically targeted antibody redirected T-cell activation
CAR T cell therapy - drugs that target CD-19
axicabtagene
ciloleucel
tisagenlecleucel
CAR T cell therapy in children
- first approved for acute lymphoblastic leukaemia paediatric and adolescent patients
- intense chemotherapy cure 80% of all paediatric
- effective treatments have been limited for pts whose cancers return, or relapse, after chemotherapy or a stem cell transplant
side effects of CAR T cell therapy
CYTOKINE RELEASE SYNDROME
occurs when a large number white blood cells are activated and release inflammatory cytokines, which in turn activate more white blood cells
lead to systemic hyper-inflammation
also
NEUTROPENIA
NEUROTOXICITY
HPV and cancer
- HPV > sexually transmitted virus spread by vaginal, anal and oral sex
- more than 100 types of HPV, at least 13 are cancer-causing
- HPV DNA detected in 90-100% of cervical cancer specimens
- HPV DNA required for development of cervical cancer
- HPV vaccination available
