1. Newer cancer therapies Immunotherapy Angiotherapy Gene therapy

2. Immunotherapy

3. Immunotherapy

4. Immunotherapy Non-specific immunotherapy Specific immunotherapy BCG
Cytokines
Cell therapy
Specific immunotherapy
adoptive
Antibody therapy
Adoptive transfer of T cells
Vaccination
Tumour-based vaccines
Virus-based vaccines
Peptide-based vaccines
others

5. Immunotherapy

6. Immunotherapy

7. Immunotherapy

8. Angiotherapy

9. Key differences in tumour vasculature
Different flow characteristics / blood volume
Microvasculature permeability
Increased fractional volume of extravascular, extracellular space

10. Angiogenesis-overview
Balance between inhibitory factors (endostatin) and angiogenic factors (VEGF, bFGF)
angiogenic factors stimulate MMPs and plasminogen activators
Degradation of basement membrane
Invasion and differentiation of endothelial cells in surrounding tissues

12. BLOOD FLOW
Before treatment
after treatment

13. MMPIs Disappointing results with matrix metalloproteinase inhibitors
Poor survival rate in phase III clinical trials against renal cell carcinoma

14. Newer cancer therapies Gene therapy
Severe Combined Immunodeficiency Disease (SCID)

15. Gene therapy
Antisense therapy (suppress gene expression) Gene augmentation (supplement defective gene)

16. Antisense therapy
compensates for genetic mutations that produce destructive proteins
Main strategies involved are
1) short stretches of synthetic DNA that target the mRNA transcripts of abnormal proteins preventing its translation OR
small RNA molecules (siRNA) used to degrade aberrant RNA transcripts

17. Antisense therapy
2) provide a gene for a protein (intracellular antibody) that can block the activity of the mutant protein
design hybrids of DNA / RNA that might direct repair of the mutant gene
Tumor necrosis therapy utilizes monoclonal antibodies targeting intracellular tumor antigens on necrotic (dead) tissue. This method overcomes some of the limitations of current antibody-based therapeutic approaches

18. Gene augmentation
most therapies simply add a useful gene into a selected cell type to compensate for the missing or flawed version or even instil an entirely new version.
Direct approach
inducing cancer cells to make a protein that will kill the cell.
Indirect approach
stimulating an immune response against selected cells or eliminating the blood supply.

19. ‘Trojan horses’ that sneak the gene into the cell
3 challenges in gene therapy
delivery
delivery
delivery
Package the gene
Protect the gene
deliver to the nucleus and release in an active form
Vectors
‘Trojan horses’ that sneak the gene into the cell

20. Vectors
Carrier molecules designed specifically to enter cells & deposit therapeutic genes Vectors can be viral or non-viral

21. METHODS OF VECTOR DELIVERY

22. Viral vector strategy
Replication & virulence genes can be substituted with therapeutic genes

23. Retroviral vectors
designed to enter cell and deposit genes Problems of retroviral therapy include Lack of cell specificity: Promiscuous: depositing genes into several cell types resulting in reduced target efficiency and unwanted physiological effects Random splicing into host DNA resulting in normal gene disruption and/or alteration in gene function

24. Adenoviral vectors do not insert into genome temporary
lack of specificity
strong immune response

25. Adeno-associated viral vectors
Integrate into genome but small in size
Nature Reviews Genetics
1; (2000);

26. Advantages non-toxic no immune response
Non-viral Vectors
Advantages non-toxic no immune response

27. Tumour-suppressor gene delivery
Nature Reviews Cancer (2001)
Vol 1;

28. Delivery of agents that block oncogene expression
Nature Reviews Cancer (2001)
Vol 1;

29. Suicide gene delivery
Nature Reviews Cancer (2001) Vol 1;

30. Conditionally replicating viruses

31. liposomes (lipoplexes)
Non-viral Vectors
liposomes (lipoplexes)

32. amino acid polymers: cationic polymers e.g. B-cyclodextrins
Non-viral Vectors
amino acid polymers: cationic polymers e.g. B-cyclodextrins

33. naked DNA artificial human chromosomes
Non-viral Vectors
Gene gun
naked DNA artificial human chromosomes

34. Successes
Cancer and the p53 gene. Researchers used a virus to carry a normal copy of the p53 gene into the abdominal and pelvic areas of women with advanced ovarian cancer. Seven of 25 women tested in California and Iowa survived more than 2 years after the therapy, despite having a terminal diagnosis.
Cancer and enzyme therapy. This type of therapy targets enzymes, or proteins, that are made by abnormal genes. Example: Gleevec, a new drug, targets an abnormal protein produced by a cancer-causing gene. The abnormal protein is necessary for some types of cancer to survive and reproduce. Gleevec blocks the action of the protein. Gleevec has been successful in chronic myeloid leukemia and in gastrointestinal stromal tumors. It is being tested in other types of cancer.
Cancer and other therapies. Advances in identifying genes have helped researchers to target other therapies. Example: Herceptin targets the HER-2 gene. In 25%-35% of breast cancers, HER-2 produces too many copies of itself, causing breast cancer cells to reproduce out of control and spread throughout the body. Herceptin blocks excess HER-2 by binding to growth receptors on the surface of the cell, causing tumors to shrink.

35. Gleevec for chronic myeloid leukaemia (CML)
CML results through a chromosomal rearrangement that fuses two genes together. This produces an oncogene that encodes an enzyme, a form of tyrosine kinase known as BCR-ABL. Unchecked production of that enzyme leads to excessive levels of white blood cells in the blood and bone marrow. that disrupts the normal production of white blood cells.
Gleevec works specifically to block the activity of that form of tyrosine kinase.