4Immunotherapy Non-specific immunotherapy Specific immunotherapy BCG CytokinesCell therapySpecific immunotherapyadoptiveAntibody therapyAdoptive transfer of T cellsVaccinationTumour-based vaccinesVirus-based vaccinesPeptide-based vaccinesothers
9Key differences in tumour vasculature Different flow characteristics / blood volumeMicrovasculature permeabilityIncreased fractional volume of extravascular, extracellular space
10Angiogenesis-overview Balance between inhibitory factors (endostatin) and angiogenic factors (VEGF, bFGF)angiogenic factors stimulate MMPs and plasminogen activatorsDegradation of basement membraneInvasion and differentiation of endothelial cells in surrounding tissues
16Antisense therapycompensates for genetic mutations that produce destructive proteinsMain strategies involved are1) short stretches of synthetic DNA that target the mRNA transcripts of abnormal proteins preventing its translation ORsmall RNA molecules (siRNA) used to degrade aberrant RNA transcripts
17Antisense therapy2) provide a gene for a protein (intracellular antibody) that can block the activity of the mutant proteindesign hybrids of DNA / RNA that might direct repair of the mutant geneTumor 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
18Gene augmentationmost 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 approachinducing cancer cells to make a protein that will kill the cell.Indirect approachstimulating 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 therapydeliverydeliverydeliveryPackage the geneProtect the genedeliver to the nucleus and release in an active formVectors‘Trojan horses’ that sneak the gene into the cell
20VectorsCarrier molecules designed specifically to enter cells & deposit therapeutic genes Vectors can be viral or non-viral
22Viral vector strategyReplication & virulence genes can be substituted with therapeutic genes
23Retroviral vectorsdesigned 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
24Adenoviral vectors do not insert into genome temporary lack of specificitystrong immune response
25Adeno-associated viral vectors Integrate into genome but small in sizeNature Reviews Genetics1; (2000);
26Advantages non-toxic no immune response Non-viral VectorsAdvantages non-toxic no immune response
27Tumour-suppressor gene delivery Nature Reviews Cancer (2001)Vol 1;
28Delivery of agents that block oncogene expression Nature Reviews Cancer (2001)Vol 1;
29Suicide gene deliveryNature Reviews Cancer (2001) Vol 1;
32amino acid polymers: cationic polymers e.g. B-cyclodextrins Non-viral Vectorsamino acid polymers: cationic polymers e.g. B-cyclodextrins
33naked DNA artificial human chromosomes Non-viral VectorsGene gunnaked DNA artificial human chromosomes
34SuccessesCancer 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.
35Gleevec 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.