L16 - Anti-cancer 4: therapeutic antibodies, biological therapies & new directions

Question 1

How can humanised antibodies be used in anti-cancer treatment ( what does the binding of the antibody do)?

Answer 1

binding of antibody - prevent interaction with cell-surface receptor OR recruit immune cells to kill antibody-bound cancer cells

Question 2

What can be conjugated to humanised antibodies?

Answer 2

toxin

radioisotope - local source of radiotherapy

Question 3

What are the 2 criteria for antigen target for humanised antibodies?

Answer 3

protein over-expressed on tumour cell surface

low level/absent in normal cells

Question 4

Why does the monoclonal antibody have to be humanised?

Answer 4

immune system would recognise as foreign if not

Question 5

How are humanised antibodies produced?

Answer 5

recombinant DNA technology

keep original CDR region but make the rest human

Question 6

What are the new developments that make antibody fragments that penetrate tissues better?

Answer 6

single chain variable region fragments (scFv)

synthesised in bacteriophage

Question 7

What are scFv antibodies?

Answer 7

single chain variable region fragments

variable region connected by by linker

Question 8

Where are scFv displayed?

Answer 8

pIII of a filamentous phage

Question 9

How are particular scFv antibodies expanded?

Answer 9

panning

Question 10

Clinical potential of humanised monoclonal antibodies?

Answer 10

huge table on slide

Question 11

are monoclonal antibodies just used for cancer?

Answer 11

NO

e.f. anti-TNFa - rheumatoid arthritis

Question 12

What us Herceptin used to treat?

Answer 12

breast cancers that DO NOT EXPRESS estrogen/progesterone receptor

OR

DO NOT respond to tamoxifen

Question 13

What does Herceptin target?

Answer 13

HER2

Question 14

Is HER2 over-expressed in breast cancer?

Answer 14

yes, 30%

Question 15

When is Herceptin most effective?

Answer 15

metastatic breast cancer

not so much in early stages

Question 16

Can Herceptin be used in combined therapy?

Answer 16

yes, with paclitaxel

Question 17

Advserse effects of Herceptin?

Answer 17

heart failure

Question 18

New development with Herceptin?

Answer 18

link emtansine to Herceptin

tubulin inhibitor usually too toxic for cells

break off from herceptin at breast cancer cells - very toxic

Question 19

What is Bevacizumab also known as?

Answer 19

Avastin

Question 20

What is Bevacizumab given with in colorectal cancer?

Answer 20

5FU

Question 21

What does bevacizumab do?

Answer 21

stops new blood vessels forming

binds to VEGF

Question 22

adverse effects of bevacizumab?

Answer 22

hypertension

intestinal bleeding

interferes with normal blood vessels

Question 23

What does Rituximab do?

Answer 23

binds CD20 expressed on B cells

Question 24

What is rituximab used to treat?

Answer 24

non-Hodgkin lymphoma

other lymphoma/leukaemia

Question 25

What is rituximab given with?

Answer 25

other anti-cancer drugs cyclophosphamaide

Question 26

side effects of rituximab?

Answer 26

hypotension | cardiac problems

Question 27

What does Cetuximab do?

Answer 27

target EGF receptor interfere with cancer cell growth, prevent EGF binding

Question 28

What is cetuximab given with?

Answer 28

Irinotecan

Question 29

What is Cetuximab used for?

Answer 29

colorectal cancer

Question 30

side effects of cetuximab?

Answer 30

fever | hypotension

Question 31

What is CTLA-4?

Answer 31

cytotoxic T cell antigen 4 negative molecule, downregulates immune response can engage with CD80/86 on cancer cell instead of CD28

Question 32

What happens when CD28 binds to CD80/86 on cancer cell?

Answer 32

completel activation and priming costimulation of immune response against cancer cells

Question 33

What is the name for Anti-CTLA-4?

Answer 33

Iplilumumab

Question 34

What is Ipilumumab?

Answer 34

fully humanised MoAb blocks CTLA-4 activates Cytotoxic T cells

Question 35

What are Anti-CTLA4 MoAbs also referred to as?

Answer 35

immune checkpoint inhibitors

Question 36

What does Ipilumumab treat?

Answer 36

melanoma

Question 37

What does PD-1 do?

Answer 37

induce apoptosis of T cells if PD-1 engages with ligand - kills T cells

Question 38

Do cancer cells overexpress PD-1?

Answer 38

yes - to kill T cells

Question 39

What is the FULLY humanised MoAb against PD-1?

Answer 39

MDX1106

Question 40

What are the humanised MoAbs that block PD-1?

Answer 40

Nivolumab | Pembrolizumab

Question 41

What is IMA901?

Answer 41

synthetic RCC-associated peptides stimulate T cells

Question 42

What is AGS003?

Answer 42

patient DCs loaded with autologous tumour RNA stimulate CD28+ memory T-cells

Question 43

What are immunotherapy approaches to RCC?

Answer 43

``` MDX1106 nivolumab pembrolizumab IMA901 AGS003 ```

Question 44

What is L-Asparaginase?

Answer 44

Bacterial enzyme depletes blood asparagine - affects tumour cells that have low asparagine

Question 45

What is L-asparaginase used for?

Answer 45

childhood acute lymphocytic leukaemia

Question 46

What is L-asparaginase used in combo with?

Answer 46

vincristine | prednisone

Question 47

Do cancer cells have high levels of asparagine?

Answer 47

NO - low levels

Question 48

What are the 2 types of IFNs?

Answer 48

Type 1 - alpha and beta Type 2 - gamma

Question 49

What were IFNs originally discovered for?

Answer 49

anti-virals

Question 50

What 2 things do IFNs do against cancer cells?

Answer 50

promote apoptosis in cancer cells stimulate immune cells to recognise/kill cancer cells

Question 51

What does IFNs are approved for viral cancers?

Answer 51

IFN-alpha2a IFN-alpha2b AIDS-related KSHV hairy cell leukaemia (retrovirus)

Question 52

How many human IFN-a genes?

Answer 52

at least 12

Question 53

side effects of high dose IFN?

Answer 53

depression | loss of energy

Question 54

What does IFN-a2 extend disease-free survial for?

Answer 54

melanoma after surgical removal of tumour

Question 55

What is IL-2?

Answer 55

T-lymphocyte growth factor

Question 56

What is IL-2 used to treat?

Answer 56

RCC and melanoma

Question 57

What is IL-2 possibly synergistic with?

Answer 57

IFN-a2 greater effects used together

Question 58

Side effects of IL-2?

Answer 58

hypotension liver damage max tolerance 14 doses

Question 59

What is GM-CSF used for?

Answer 59

reconstitute myeloid blood cells after HSCT

Question 60

How can GM-CSF be useful in cancer treatment?

Answer 60

stimulate cellular immune system synergistic with IL-12 stimulation of immune cells

Question 61

How does IL-12 help cancer treatment?

Answer 61

Stimulate B-cells, T-cells and NK cells acts as IMMUNOSTIMULANT