CANCER IMMUNOTHERAPY P1

Question 1

cancer associated antigens

Answer 1

• neoantigens
• overexpresssed self antigens
• self antigens that are expressed during embryonic development by are not expressed or are expressed at low levels after birth

Question 2

neoantigens

Answer 2

result from gene mutations in cancer cells and have not been seen previously by the immune system

Question 3

how can antigens on tumours initiate an immune response

Answer 3

cancer-associated antigens mark cancer cells as abnormal or foreign and can cause killer T cells to mount an attack against them

Question 4

cancer cell strategies to evade detection by the immune system

Answer 4

• 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)

Question 5

tumour associated macrophages (TAM)

Answer 5

• 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

Question 6

classical immunotherapy

Answer 6

the treatment of disease by inducing, enhancing or modulating an immune response

Question 7

cancer immunotherapy

Answer 7

• antibody-based therapy
• vaccines
  cell based therapies>
• dendritic cells
• T cells

Question 8

antibodies in cancer immunotherapy

Answer 8

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

Question 9

rituximab (Rituxan)

Answer 9

• 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

Question 10

rituximab indication

Answer 10

non-Hodgkin’s lymphoma
chronic lymphocytic leukaemia (CLL)
cancers which develops in B lymphocytes

Question 11

side effects of rituximab

Answer 11

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

Question 12

rituximab mechanism of action

Answer 12

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

Question 13

main side effect of herceptin

Answer 13

cardiac dysfunction

Question 14

HER2

Answer 14

activates MAPK and PI3K pathways which increases cell growth, survival, adhesion, migration, and differentiation

Question 15

Herceptin receptor

Answer 15

Herceptin binds to HER2 receptor

Question 16

herceptin in HER2-overexpressing metastatic breast cancer

Answer 16

• in combination with paclitaxel for first-line treatment
• single agent in patients who have received one or more chemo regime

Question 17

administration of herceptin

Answer 17

IV infusion
SC injection - early breast cancer only

breast cancer every 1 or 3 weeks up to 1 year
gastric cancer every 3 weeks

Question 18

immune checkpoint proteins

Answer 18

• 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

Question 19

CTLA-4

Answer 19

cytotoxic T-lymphocyte-associated protein 4-receptor

inhibitory checkpoint receptor protein expressed on T cells

Question 20

Ipilimumab

Answer 20

• antibody against CTLA-4 expressed on T cells
• ipilimumab blocks negative signalling from CTLA-4

Question 21

process in which ipilimumab blocks CLTA-4

Answer 21

• 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

Question 22

administration of ipilimumab

Answer 22

intravenous infusion 3mg/kg every 3 weeks for 4 doses

Question 23

common side effects related to inflammatory responses

Answer 23

fatigue
diarrhoea
skin rash
vomiting

Question 24

ipilimumab indication

Answer 24

• 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

Question 25

PD-1

Answer 25

checkpoint receptor protein expressed on T cells and B cells

Question 26

PD-L1/PD-L2

Answer 26

- 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

Question 27

which cancers is PD-L1 expressed

Answer 27

- especially in NSCLC - melanoma - renal cell carcinoma - gastric cancer - hepatocellular/cutaneous - various leukaemias - multiple myeloma

Question 28

the cancer immunity cycle blocked by PD-L1/PD1

Answer 28

1. tumour cells produce mutated antigens that are captured by dendritic cells 2. the dendritic cells prime T cells with tumour antigen and stimulate the activation of cytotoxic T cell 3. activated T cells then travel to the tumour and infiltrate the tumour environment 4. the activated T cells recognize and bind to the cancer cells 5. the bound effector T cells release cytotoxins, which induce apoptosis in their target cancer cell 6. the cancer cell can block the T-cell attack through PD-L1 (cancer cells) binding to PD1 on T-cell

Question 29

how do tumours use PD1-mediated immune suppression to avoid immune surveillance

Answer 29

- 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

Question 30

proinflammatory molecules that induce PD-L1 expression

Answer 30

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

Question 31

regulation of PD-L1 expression by GM-CSF and VEGF

Answer 31

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

Question 32

PD-1 inhibitors

Answer 32

PROGRAMMED CELL DEATH PROTEIN 1 pembrolizumab Nivolumab

Question 33

PDL-1

Answer 33

PROGRAMMED DEATH-LIGAND 1 atezolizumab avelumab durmalumab

Question 34

microsatellite instability and mismatch DNA repair

Answer 34

- 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

Question 35

cause of defects in MMR

Answer 35

defects in MMR are associated with genome-wide instability and increased TMB

Question 36

Pembrolizumab

Answer 36

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)

Question 37

side effects of checkpoint inhibitors

Answer 37

diarrhoea pneumonitis rashes and itchiness problems with some hormone levels kidney infections

Question 38

administration of checkpoint inhibitors

Answer 38

- 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

Question 39

chimeric antigen receptors T-cell therapy (CAR-T)

Answer 39

- 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

Question 40

CAR T cell therapy - drugs that target CD-19

Answer 40

axicabtagene ciloleucel tisagenlecleucel

Question 41

CAR T cell therapy in children

Answer 41

- 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

Question 42

side effects of CAR T cell therapy

Answer 42

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

Question 43

HPV and cancer

Answer 43

- 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