The University of Louisville’s publication UL News recently reported a finding by its research team regarding an immune checkpoint molecule. The molecule had been developed for cancer immunotherapy but when administered by itself the researchers found that it also protects against future development of other types of cancer.
Cancer uses various means to evade the immune system including checkpoint inhibitors. Immune checkpoint inhibitors and stimulators regulate the immune system. They work in the same fashion as the gas pedals or brakes in an automobile.
The immune system has the ability to distinguish between normal cells and “foreign” cells. In this way, it attacks the foreign cells but does not attack the normal cells. This occurs by the immune system’s use of “checkpoints”. These checkpoints are specific cells that must be activated or inactivated in order for the immune system to begin its response. On the other hand, stimulators provide the accelerator function which assists in the body’s fight against cancer.
The FDA has already approved drugs for several types of cancer that block the action of immune checkpoint inhibitors. Haval Shirwan, Ph.D., a professor at the U of L Department of Microbiology and Immunology and the U of L Institute for Cellular Therapeutics explains that they are now focusing on immune checkpoint stimulators.
Researchers have had success in improving the therapeutic efficacy of various cancer vaccines by using the protein molecule SA-4-1BBL in pre-clinical animal models. This increases the effectiveness of CD8+ T cells which are immune cells that destroy tumors. SA-4-1BBL is a natural ligand (molecule) and does not cause toxicity. Also, autoimmunity is less of a concern because SA-4-1BBL activates innate (natural) immune cells.
An Unexpected Event
The researchers reported that when they treated normal healthy mice with the molecule SA-4-1BBL alone, it protected the mice later on when they were exposed to various types of tumor cells.
Professor Shirwan further explains that this molecule can generate an immune response that locates rare tumor cells and then eliminates cancer before it takes effect.
The normal procedure has been that the immune system must first:
- be exposed to a tumor
- recognize that the tumor is dangerous
- generate a tumor-specific response, then
- eliminate the tumor
Professor Shirwan describes the discovery as being very surprising because the immune system does not see the tumor and therefore it is not actually responding to the presence of a tumor.
Further research indicates that a tumor immune surveillance system is generated by SA-4-1BBL through activation of CD4+T cells and natural killer cells. These cells protect the mice from various cancers that try to invade the body. This function may exhibit the molecule’s role in cancer immunoprevention.
Further Discovery
Cancer Research recently published an article that describes how mice that had never had cancer previously were given SA-4-1BBL. Then the mice were exposed to lung and cervical cancer tumor cells at various intervals.
The results showed that the mice exhibited protection against tumor development. The greatest protection occurred two weeks after they received treatment with SA-4-1BBL. The effect of the treatment continued for eight weeks.
Professor Shirwan said they believe that this is the first study showing how an immune checkpoint stimulator, as a single agent, is able to activate an immune system surveillance mechanism that protects against certain types of tumors.
Additional Testing
The researchers discovered that CD8+T cells were not required for protection but when CD4+T and natural killer cells were eliminated in the mice, protection failed. This was an indication that these two cell types were necessary for protection. However, the fact that CD8+T is not necessary for this scenario is a clear indication that the process is not one of conventional acquired immunity.
Clinical testing for cancer immunotherapy is currently being conducted on several antibody molecules as immune checkpoint stimulators. Thus far the FDA has not approved anything that is associated with sending positive signals to the T cells.
Professor Shirwan said that “Another big surprise” was the researcher’s observation that an antibody [which is meant to fight off “foreign invaders”] did not give protection against tumors although that same receptor was targeted by SA-4-1BBL. According to Professor Shirwan, “this demonstrates the unique and desired features of SA-4-1BBL for cancer immunoprevention.”
He further explained the difficulty of holding trials with a sufficient number of participants. He is hoping that the newer screening technologies and genetic tools to identify high-risk subjects will give them the opportunity to test the SA-4-1BBL molecule in people who are at risk for certain cancers.
