Vaccine angiogenesis

Question 1

What was one of the first targets for angiogenesis that was discovered?

Answer 1

VEGF

Question 2

What is Avastin and is it successful?

Answer 2

Avastin was developed to target VEGF in angiogenesis. The effects were still rather limited (+- 3-4 months). After those 3-4 months there was resistance, because other molecules like VEGF started taking over the function (like FGF).

Question 3

How can you find new targets for angiogenesis?

Answer 3

Look for genes that are not expressed in the healthy body: look at embryonic genes. Compare embryonic cells with healthy cells. Then look if the genes that are only expressed in embryonic cells, but not healthy cells are also expressed in tumour cells.

Use deep sequencing to look for genes that are expressed in tumour vasculature, but not in healthy cells. Problem: difficult to find.

Look at markers that are proliferating, but you don’t want to target every proliferating cell in the body because then you wouldn’t have any gut epithelium left.

Question 4

What is Vimentin and how can it be used to target angiogenesis?

Answer 4

Vimentin is probably to keep organelles in the right place and was overexpressed in tumour cells and is expressed outside of the cells instead of only in the cytoplasm. Targeting of Vimentin inhibits angiogenisis. Tumour growth is significantly inhibited in the presence of anti-Vimentin Abs, but not with control Abs. Body weight of mice also didn’t change, so it is probably safe!

Question 5

Why would you use vaccination to target angiogenesis?

Answer 5

Why use vaccination?
•Polyclonal antibodies neutralize better than monoclonal
•Autologous antibodies have better penetration into tissues
•Multiple targeting possible
•Vaccination is less invasive
•Long-term efficacy (12-18 months)
•Vaccination is less expensive

However, until now cancer vaccines are only sparsely developed.

Question 6

Why is it difficult to make a vaccine against vascular antigens to target angiogenesis?

Answer 6

Because they are self-antigens and it is very difficult to make a vaccine against self-antigens.

Question 7

How does vaccination against a self-antigen work?

Answer 7

1. A conjugate of a self-antigen and a non-self antigen is made.
2. This conjugate is taken up by an APC.
3. The antigen (self and non-self separately) is presented on MHCII.
4. A non-self reactive T helper cell recognizes the non-self antigen.
5. Clonal expansion of this non-self-reactive Th cell.
6. An autoreactive B-cell receives help from the Th cells directed against the non-self peptide. There is interaction of the T-cell receptor and the MHC&antigen.
7. Clonal expansion of auto-reactive B-cells.
8. Production of auto-antibodies

Question 8

What is the iBoost technology?

Answer 8

iBoost technology:

1. Produce conjugate vaccine
2. Make vaccine protein containing truncated foreign antigen thioredoxin (TRXtr)
3. Less anti-TRXtr antibodies and more anti-self-antigen Abs!

Question 9

What is different in the vaccination schedule when testing a conjugate against a tumour?

Answer 9

Because tumour grows very fast in this model, vaccination starts before tumour.
This gives good results and safety in different mouse models. Also absence of long-term toxicity.

Tested in dogs with bladder cancer (only treatable with operation). Worked very good, but n=2 now and they are +1 month over life expectancy (research still ongoing).

Question 10

What markers for angiogenesis can be used for cancer prevention?

Answer 10

Markers that are expressed before malignancy, but not in a healthy/normal state.