Wednesday, October 11, 2017

What is Cancer Immunotherapy

Cancer is a disease that can impact any tissue in the body.  When normal tissue cells become cancerous (malignant), they lose some of the fundamental properties of the tissue cells they originated from.  They also grow out of control and ultimately spread (metastasize) to other parts of the body where they bring chaos and instability.  The transformation that normal cells undergo when they become cancerous is known to be a result of genetic changes to the cells complement of DNA.  In some types of cancer there is a definitive hereditary genetic component as in certain types of breast cancer, for example.  A widely accepted model for the transformation of normal cells to the cancerous state involves spontaneous somatic mutation(s).  There are many man-made organic chemicals in the environment that are known to initiate the onset of cancers; these are collectively referred to as carcinogenic compounds.  Carcinogens have also been shown to be mutagens – chemical agents that cause genetic mutations.

The conventional therapies that are applied to a patient that presents with cancer has generally involved the use of chemotherapeutic drugs and/or radiation treatment.  The therapies that employ these agents are referred to as a shotgun approach; since, they do not discriminate between normal and cancer cells   Chemotherapeutic drugs target any cell that is actively dividing and radiation damages cellular DNA that results in cell death.  Although these techniques have become refined over the years, they still suffer from this serious limitation.

This is where Immunotherapy offers an important advantage; because, treatments that use immunotherapy specifically target cancerous cells.  What follows is a discussion of the rationale of some of these approaches.

Succinctly stated, “Immunotherapy is treatment that uses certain parts of a person’s immune system to fight diseases such as cancer.” This can be accomplished in a number of ways.  The patient’s natural immune system can be enhanced to better target cancerous cells.  This is possible; because, an important component of the immune system is referred to as, “the cancer surveillance system.”  Certain subsets of cells in the immune system are designed to target any cell that possesses antigens on their cell surface that are indicative of the fact that it has been transformed,  These antigens indicate to the immune system that the cell is no longer self and thereby becomes subject to destruction.  Another approach involves the addition of human manufactured immune system – related proteins.  This capability is possible on account of the fact the cellular manufacture of unique proteins depends upon a particular gene   Technologies are in wide use that can insert a particular human gene into bacteria in culture and have the bacteria manufacture the human protein product.  This approach has made possible the mass production of human insulin and human growth hormone, for example.  In addition, some types of immunotherapy are also referred to as biologic therapy or biotherapy.

The methodologies that are currently being tested and employed can be classified in the following way –

·        Monoclonal Antibodies  - Once an antigen specific for a certain type of cancer has been isolated, antibodies can be manufactured that are specific to that antigen.  This antibody can then be introduced into the patient with that cancer.  Once the circulating monoclonal antibodies bind to cancer cells, this triggers the immune system to target those cells and destroy them.
·        Immune Checkpoint Inhibitors – The immune system is a very powerful system that has built-in safeguards to keep it under rigorous control i.e. to make it possible to destroy transformed cancerous cells leaving normal cells intact.  This is accomplished by immune checkpoint factors.  These factors are on certain cells in the immune system and need to be activated or inactivated to trigger the immune response.  Some cancer cell types can use this system to prevent it from being used against them.  For these cancers, checkpoint inhibitors are designed to interact with these factors and render them ineffectual; thereby, improving the potency of the immune system targeting cancerous cells.
·        Cancer Vaccines - Cancer vaccines are being developed to treat or even prevent the onset of certain types of cancer.

The following is a table that summarizes some of these data –

Type of Cancer
Methodology Employed
Rationale
Chronic Lymphocytic Leukemia (CLL)
Monoclonal Antibodies
The monoclonal antibody that has been used targets the CD 20 cell-surface antigen that is in high concentration in some forms of this disease.
Advanced Colorectal Cancer (CRC)
Immune Checkpoint Inhibitors
Many inhibitors are currently being produced and tested.  Some benefit has been shown with certain cancers that are particularly difficult to treat.
Cervical, Advanced Prostate and Bladder Cancer
Cancer Vaccine
Cervical cancer, for example, is known to be caused by the human papilloma virus (HPV).   Therefore, a vaccine that targets this virus can prevent the onset of cervical cancer


It should be remembered that the use of immunotherapy in treating cancer remains in its infancy and requires additional research efforts to improve its efficacy and diminish known side-effects.  However, it is an exceedingly promising approach and is worthy of continued research efforts and support.

Wednesday, August 23, 2017

Melting Permafrost in Alaska

It is my fervent hope that the total solar eclipse that has received so much attention is a reminder of our real relationship with this our remarkable planet and its place in the cosmos. For we need to pay close attention to the degree to which our behavior is changing the planet. The following may help illustrate this (from the New York Times) - Alaska's Melting Permafrost

Wednesday, August 16, 2017

The Biochemistry of Nitric Oxide and its Application to Medicine

Nitric oxide (see illustration below) is a highly reactive compound.  Nitrogen (N2) (see illustration below constitutes 78 % of the ambient air; whereas, the concentration of NO in the lower atmosphere has been determined to be within the range of .4 to 71 parts per billion (ppb).


Atmospheric Nitrogen

 
NO was discovered to play an important role in human metabolism.  Within the human body, the enzyme responsible for its production is nitrogen oxide synthase (NOS) (see diagram below) and exists in a number of forms (isoenzymes) – one residing within epithelial cells (eNOS) and another residing within neuronal cells (nNOS).  Once NO is produced, it functions as a chemical messenger that influences a wide variety of cellular processes.  The general scheme of its metabolism is represented below.
Enzymatic Synthesis of NO

NO Metaobolism

Within the human body, NO provides protection against cardiovascular diseases on account of its roles in the regulation of blood pressure.  In addition, NO inhibits the aggregation of platelets and leukocyte (white blood cell) adhesion and thereby diminishes the likelihood of blood clots.  It appears that areduced availability of NO plays a role in the onset of cardiovascular disease.


For all the reasons cited above, NO seems to be vitally important in the maintenance of the continued health of the human cardiovascular system.  The following diagram demonstrates the various stages of NO metabolism in which particular drugs can increase the bio-availability of NO.  This approach to the manufacture and use of particular drugs that can target NO metabolism is of special interest in the practice of medicine.

Bio-availability of  NO Enhanced by the Application of Particular Drugs

Friday, July 14, 2017

Vaccine Development for the Lassa Virus

The Lassa virus is the causative agent for Lassa fever that is serious ailment sometimes leading to death.  This disease is a so-called “hemorrhagic disease.”  Lassa fever is prevalent in West Africa   Currently there is no vaccine available for this disease.

According to the Center for Disease Control and Prevention (CDC): “Signs and symptoms of Lassa fever typically occur 1-3 weeks after the patient comes into contact with the virus. For the majority of Lassa fever virus infections (approximately 80%), symptoms are mild and are undiagnosed. Mild symptoms include slight fever, general malaise and weakness, and headache. In 20% of infected individuals, however, disease may progress to more serious symptoms including hemorrhaging (in gums, eyes, or nose, as examples), respiratory distress, repeated vomiting, facial swelling, pain in the chest, back, and abdomen, and shock. Neurological problems have also been described, including hearing loss, tremors, and encephalitis. Death may occur within two weeks after symptom onset due to multi-organ failure.

The most common complication of Lassa fever is deafness. Various degrees of deafness occur in approximately one-third of infections, and in many cases hearing loss is permanent. As far as is known, severity of the disease does not affect this complication: deafness may develop in mild as well as in severe cases.

Approximately 15%-20% of patients hospitalized for Lassa fever die from the illness. However, only 1% of all Lassa virus infections result in death. The death rates for women in the third trimester of pregnancy are particularly high. Spontaneous abortion is a serious complication of infection with an estimated 95% mortality in fetuses of infected pregnant mothers.
Because the symptoms of Lassa fever are so varied and nonspecific, clinical diagnosis is often difficult. Lassa fever is also associated with occasional epidemics, during which the case-fatality rate can reach 50% in hospitalized patients.”

The Lassa virus is a member of the class of single-stranded RNA viruses within the arenavirus family (see image below).  It possesses a rather simple structure with only one glycoprotein on its surface – GPC.  The function of this protein is to preferentially bind to its host cell target that are primarily the epithelial cells that line the blood capillaries.



Dr Kathryn M. Hastie from and her colleagues from the Scripps Research Institute in La Jolla, California were interested in studying the binding of neutralizing antibodies obtained from a human survivor of Lassa fever with GPC in order to gain some insight in regards to the structure of GPC and the virus’ manner of entry into the host cell.  Elucidating this mechanism would provide significant insight into the development of an effective vaccine against this horrific disease.

GPC in its configuration on the virus particle (virion) exists as a trimer each containing a receptor bind subunit (GP1) and a transmembrane subunit (GP2).  Once binding via GPC is successful and the viral RNA successfully gains entry into the host cell, it commandeers the host’s cellular machinery within the cytoplasm leading to the production of infectious virions – a process that leads to cell death and release of the viral progeny that go on to infect neighboring cells.
   

In order to elucidate the structure and organization of GPC on the viral surface, the research team studied, “more than 100 antibodies from human survivors of Lassa fever.”  This investigation lead to the discovery that the majority of antibody responses targeted the entire GPC assembly rather than individual subunits.  High resolution images of the antibody-GPC complex were derived from X-Ray crystallography.  These data provide information essential for the development of an effective vaccine for this virus.

Wednesday, April 12, 2017

Melting Ice in Antartica

Another example of why Climate Change is a cause for our deepest concern. It certainly deserves our undivided attention. Any government on this planet that attempts to deny this reality is deeply suspect in my judgment.

Tuesday, March 14, 2017

Strategy for the Preferential Elimination of Cancer Cells

The cell surface of mammalian cells is populated with a wide array of proteins that are involved in many aspects of cell-cell communication that is absolutely essential for life. When a normal tissue cell is transformed into a cancerous cell, it often exhibits proteins on the surface that indicate that it has become aberrant – no longer subject to the usual controls that inhibit unrestrained growth.

These “marker” proteins are frequently used to identify cancerous cells and therapeutic strategies are being studied to exploit the presence of these proteins to preferentially kill tumor cells. However, in some types of cancer no unique markers are identifiable.

In order to circumvent this obstacle, Zhiyu Wang from the University of Illinois recently reported on a methodology to positively identify cancer cells that relies on a different approach. Their research strategy can be described in the following way.

 They incubated tumor cultured cells with a class of compounds called sugar azides (structure shown below). The compound DBCO (structure shown below) binds preferentially to sugar azide on the cell surface. In order to ensure that the sugar azide appears only on cancer cells, the researchers modified the sugar azide with protective group that could only be removed with an intracellular tumor-specific enzyme. Once the DBCO-sugar azide complex is on the cell surface, it can be exploited to deliver cancer treating drugs or agents that can used to provide important imaging information.


Azide Sugars


DBCO

This methodology has been successfully employed against colon cancer tumors and metastatic breast cancer in the mouse animal model.