Bench to Bedside | March 2016

A Molecular Balancing Act to Fight Autoimmune Disease and Cancer

Wayne Hancock, MBBS, PhD, has spent more than a decade trying to strengthen the activity of certain cells in the body that could help control conditions including autoimmune diseases and organ transplant rejection. When his efforts inadvertently weakened those cells, he used to throw those failed results away, along with the experimental drugs that produced them.

“Now we’re a bit cleverer, and we’re using them for cancer,” said Dr. Hancock, chief of the Division of Transplant Immunology at The Children’s Hospital of Philadelphia, and professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania.

Dr. Hancock was recently awarded two new grants from the National Institutes of Health to discover drug targets and therapies to manipulate these cells, called T-regulatory cells or Tregs, for each of these opposite effects.

“If we have insufficient numbers of Tregs or they don’t work properly, we get multiple sclerosis, diabetes, asthma, and autoimmune diseases,” Dr. Hancock said. “If we have too many, that might predispose us to cancer. We want to live in that balanced area where there’s not too much and not too little.”

Increasing Treg Activity to Dial Down Excess Immune Response

Tregs play an important role by quieting the immune response at times when it gets overzealous and attacks healthy cells and tissues instead of only foreign materials, a situation that occurs in autoimmune diseases and after a transplant procedure.

Injecting Treg cells into the body is one popular experimental approach to treating these conditions. The NIH has dedicated millions of dollars into clinical trials for these Treg cell therapies.

“I think that’s short-sighted,” Dr. Hancock said. “Even under ideal conditions, these are short-lived cells, and in inflammatory conditions they’re even shorter lived.”

Instead, he aims to make Tregs stronger through drug therapies.

In the first of his newly funded studies, he is testing and developing potential drug therapies in a mouse model that could increase the activity of Treg cells by increasing the activity of the protein Foxp3 within them, as well as further describing the molecular mechanisms affecting the activity of Foxp3 in Treg cells.

Foxp3 is a transcription factor, a type of molecule that controls which genes are expressed in the cell. The presence and activity of Foxp3 is what makes a Treg a Treg, and not any other type of cell. Even in Treg cells, though, the activity of Foxp3 is still repressed most of the time. Dr. Hancock has identified some of the molecules that put the brakes on Foxp3 in Treg cells, and he is testing drug compounds that may take away or block those braking mechanisms.

Specifically, in previous research Dr. Hancock identified the molecules HDAC7 and HDAC9 as brakes that suppress another family of transcription factors called Mef2. Mef2 molecules activate the expression of Foxp3. Working with collaborators at other institutions, he has identified several drug compounds that inhibit these HDAC molecules, and in the new project he will develop and further test these potential drugs.

He also aims to further describe the mechanisms by which HDAC and Mef2 molecules regulate Foxp3 in Treg cells by finding out which Mef2 molecule or molecules in particular may be more important to the process. This would help narrow down the target to select drugs that act precisely to increase Treg activity, with less risk of side effects on other cells and processes.

Decreasing Treg Activity to Dial Up Immune Response to Cancer

On the opposite side of the balancing act, Dr. Hancock is researching ways to make Tregs function worse, thereby dialing up the body’s immune reactivity to cells and materials that seem foreign.

“Degrading Treg function sounds like an unhealthy proposition,” Dr. Hancock said.

In fact, wiping out Treg functions entirely would be unwise, because it would cause the immune system to attack the body with such potency that a person would die of autoimmune disease.

“But it turns out that in cancer, many cancer therapies are less effective because the immune system is not active against the tumor. If you can make the immune system stronger, you can make the cancer therapy more effective.”

Dr. Hancock’s second newly funded NIH grant allows him to continue preclinical screening of potential drug compounds that have shown promise decreasing the activity of Tregs.

In the first phase of this research, Dr. Hancock has already shown that tumors only shrink in animals with normal immune systems that receive these compounds, and not in immunodeficient animals, suggesting that it is indeed the immune modulatory effect of the drug that prompts the body to attack the tumor. With the next phase of funding, awarded to Progenra Inc., as a phase 2 Small Business Innovation Research project with Dr. Hancock as the principal academic partner at CHOP, he is working to further optimize the compounds and to identify their mechanism of action.

“Immuno-oncology, modulating the immune response to tumors, is now the hottest area in cancer work,” Dr. Hancock said. “This is a completely new spin on it, so it will be very exciting if it turns out to work. With the transplant work, people are putting all their eggs in Treg cell therapy, so, again, we’re the lone voice in the wilderness. I think with time pharmacologic regulation of Treg will have significant impact because the experimental work is very compelling.”


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