This image shows the SA-4-1BBL (green color) bound to its receptor on an immune cell (red color) to start an immune activation cascade to fight cancer. | Photo courtesy of UofL

A University of Louisville research team has found evidence that priming the immune system to fight the future development of various cancers is possible.

The accidental discovery occurred when the team injected healthy mice with a molecule that it created called SA-4-1BBL and discovered that the animals were protected when exposed to different types of tumor cells.

Haval Shirwan, a professor in the UofL Department of Microbiology and Immunology who co-leads the team with fellow UofL researcher Esma Yolcu, said the discovery is a revolutionary one.



In this Insider Louisville Q&A, Shirwan, who’s also with the UofL Institute for Cellular Therapeutics, explains more about the discovery, which was reported earlier this month in the journal Cancer Research. The interview was done by email and edited for brevity.

Insider Louisville: How and why did you go about creating the recombinant protein molecule known as SA-4-1 BBL? Was the molecule created in a test tube or a Petri dish and what is it made up of?

Haval Shirwan is a professor in the University of Louisville Department of Microbiology and Immunology and the UofL Institute for Cellular Therapeutics. He and fellow UofL researcher and co-author Esma Yolcu have ownership in the start-up FasCure Therapeutics, which has an option to license the SA-4-1BBL molecule from UofL for commercial development, according to the university. | Photo courtesy of UofL

A. We knew that the natural form of this molecule, 4-1BBL, a protein, plays an important role in stimulating the immune response against infections. There was also scientific evidence that this molecule may play a role in immune responses against cancer.

However, the natural 4-1BBL molecule exists as a cell surface attached protein and is only functional in that manner. We wanted to create a novel form, SA-4-1BBL, that is functional as a cell-free protein so that we can use it as a biologic for injections. We created a synthetic DNA that codes for the protein and made the protein in insect cells in (a) test tube. The protein is then isolated from the insect cells and used for injections.

IL. How long have you been conducting the research?

A. We have been working with SA-4-1BBL to be used as the immune stimulant component of therapeutic vaccines against cancer for about 12 years.

IL. Was the original idea to use this molecule for immunotherapy purposes to get one’s own immune system to fight existing cancerous tumors? 

A. Yes.

IL. How did you determine that the molecule could actually prevent the development of existing cancers, at least in mice?

A. In a study designed to test the therapeutic efficacy of a vaccine against cancer, a group of mice were injected with this molecule only to serve as a negative control, i.e. we expected the mice in this group would develop tumors in a normal fashion. To our biggest surprise, the outcome was exactly the opposite of what we had expected: animals treated with SA-4-1BBL alone did not develop tumors.

IL. Is that a revolutionary discovery — or maybe the beginning of a potentially revolutionary discovery — that could be adapted to humans in a beneficial way? 

A. We think this is a revolutionary discovery from two perspectives. First, it provides direct evidence for the notion of  “cancer immunosurveillance.” Individuals develop cancerous cells on a continuous basis, but not everyone succumbs to cancer. It was suggested a long time ago that this is because of the immune system eliminating newly arising cancerous cells and that the individuals developing cancer have an issue with their immune system fighting the cancer. Now, our data provide direct evidence for “cancer immune surveillance” since mice treated with SA-4-1BBL had never seen the tumor cells with which they were challenged.

Second, our data show that one can train the immune system to search for cancer cells and eliminate them before cancer takes hold in the body. This provides new opportunities to focus on cancer immunoprevention, rather than therapy, that is much more challenging. Given a lot of similarities between the mouse and human immune responses to cancer, we think our concept can be adapted to the human setting. Indeed, the immune checkpoint blockers that work so effectively in the clinic were first tested in mice. The Nobel Prize in medicine was given to that discovery last year.

IL. Would the cancer-preventive effect extend beyond cervical and lung cancer tumors or be limited to those? 

A. Extends beyond those tumors.

IL. Are there any other known molecules or therapies that perform in this preventive way? Would the HPV vaccine be one, for example? 

A. We are not aware of preventive approaches that work in the way our molecule works. HPV is a vaccine to a specific tumor. Our discovery shows that we can generate a response to various tumor types. That is a fundamental difference with significant clinical ramifications.

IL. Did the mice experience any side effects or adverse effects from the treatment? 

A. There were no adverse effects under the conditions used.

IL. Is the hope that one day SA-4-1 BBL could someday be developed into a pill or a vaccine that one would receive routinely like getting a flu shot or a series of HPV shots, or might it be given to someone hoping to prevent a cancer recurrence?

A. This is an important issue that we need to investigate. However, our data would suggest a scenario of flu shots.

IL. What further study or research is needed to prove SA-4-1BBL’s effectiveness and usefulness to humans? 

A. We are in the process of testing this molecule in some other pre-clinical models relevant to the human setting, followed by the production of clinical quality SA-4-1BBL, extensive toxicity studies, and a new investigational drug application to FDA for human clinical trials.