Newer cancer therapies Immunotherapy Angiotherapy Gene therapy

Immunotherapy

Immunotherapy

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

Immunotherapy

Immunotherapy

Immunotherapy

Angiotherapy

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

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

BLOOD FLOW Before treatment after treatment

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

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

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

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

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

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.

‘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

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

METHODS OF VECTOR DELIVERY

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

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

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

Adeno-associated viral vectors Integrate into genome but small in size Nature Reviews Genetics 1; 91-99 (2000);

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

Tumour-suppressor gene delivery Nature Reviews Cancer (2001) Vol 1; 130-141

Delivery of agents that block oncogene expression Nature Reviews Cancer (2001) Vol 1; 130-141

Suicide gene delivery Nature Reviews Cancer (2001) Vol 1; 130-141

Conditionally replicating viruses

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

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

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

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.

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.