Molecular Medicine. Cancer cure in sight.

As the molecular mechanisms of various diseases are being unraveled, cures for these diseases are being discovered and put in use. Perhaps the most exciting (and potentially useful) of the coming cures is the use of the immune system to fight viral diseases and cancer.

Using immunology to PREVENT infection.
Using immunization to prevent infection has been around quite a while. However,  certain viruses and even infectious bacteria had escaped this method for one reason or another. These diseases are now being targeted by the newer uses and techniques of immunology. There have been several methodological breakthroughs responsible for these advances:

1. easier and quicker sequencing of specific proteins (such as viral coat proteins) .
2. easier and quicker methods of producing the DNA sequence coding for such proteins.
3. production of plasmids that contain the code for all or part of the DNA that codes for such proteins.
4. introduction of the pure DNA by electroporation. This method does away with the side effects of vaccination.

This type of use of immunology to prevent infection is PREVENTIVE.

Using immunology to FIGHT infection.
Once infection sets in, it can be fought by injecting monoclonal antibodies against the causative agent. A couple of American Ebola victims were cured by giving them (injecting them) with antibodies. However, monoclonal antibodies are not cheap. Far easier and cheaper is the preparation of DNA plasmids that code for the specific antibody.

Inovio, for example, is working on a serum to immunize against Ebola (it is in P1 now) as well as working on preparing a DNA plasmid that codes for an antibody that neutralizes the Ebola virus. Such a DNA is called a dMAB.

Using immunology to fight cancer.
There is no doubt that fighting tropical disease (Ebola, chicungunya and malaria) will be an important contribution to the health of people of the tropics. Inovio does have a P1 human study for Ebola and has the plasmids for chicungunya and malaria, but will  not do studies for the latter two unless government steps in with financing as it did for Ebola.

Fighting cancer is another matter. Inovio has three types of studies, which reflect the state of art in fighting cancer with immunology. The principal in using immunology for this purpose is to find a protein that is unique to the cancer cell(a marker) and attack it with killer T-cells.

1. One such marker is the Human Papillary Virus or HPV. Inovio has finished a P2 study against cervical pre-cancer. The electroporated DNA led to the regression of the disease in 49% of patients (vs 30% in controls) and got rid of the virus in 40% vs 14% in controls. P1 studies are under way using the same DNA plasmids to treat head, neck and aerodigestive cancers (all caused by HPV).

2. Using Human Reverse Transcriptase(hTERT) as a marker. hTERT appears in 85% of human cancers and Inovio has a P1 study with breast, lung and pancreatic cancers.

3. Using the control of the killer  T cells as a marker.

Killer T cells are highly regulated both to activate them and to inactivate them. There are two important points to be made here:1. normally, the T cells are not turned on to avoid autoimmune disease. This precludes immunizing the T cell against inhibition. 2. When inhibition is released, therefore, it needs to be done on a temporary basis. Thus, the choice is either an organic compound or a monoclonal antibody. Both disappear rather quickly.

The control of the action of T cells.

Some of this control is achieved through the PD1 pathway. PD1 is the Programmed Cell Death protein. It is coded for by the PDCD1 gene. PD1 is an IgV protein. It has a part that is extracellular, another part that is anchored in the cell membrane and a third part that is an intracellular part that has two phosphorylation sites on it. PD1 promotes apoptosis (cell death) in antigen-specific T cells in the lymph nodes while reducing apoptosis in regulatory T cells. Thus, PD1 is an immune check point, where removal of own cells is inhibited and this prevents auto immunity.

Cancer cells evade removal from the body by overexpressing a couple ligands (PDL-1 and PDL-2) which turn off PD1. Bristol Mers has an antibody drug (Nivolumab) that inhibits PDL-1. Treatment with this gave good results in a P2 study in non-small-cell lung cancer, melanoma and renal cell cancer, but not colon and pancreatic cancer. Merck used its own checkpoint inhibitor in melanoma, lymphoma and mesothelioma.

Inovio has the dMAB plasmids against both PD1 and PDL-1 and was just awarded a patent for it.
Finally, Inovio has a P1 study against cervical cancer where the anti-HPV plasmid is fortified with an HL-12 T-cell stimulator.

Here is a schematic of the PDL-1 pathway.

PD-L1 binds to 2 receptors: B7.1 AND PD-1³

PD-L1

Broadly expressed in multiple tissue types, including hematopoietic, endothelial, and epithelial cells^1,4

B7.1

Receptor expressed on activated T cells and dendritic cells³

PD-1

Receptor expressed primarily on activated