Clues for a cure from pregnancy

Shernan Holtan

Shernan Holtan, M.D., part of the U’s hematology and oncology faculty and recipient of Masonic support, has had a longtime fascination with using the immune system to fight cancer and a passion for making blood and marrow transplantation successful.

Holtan’s research focus is stopping graft-versus-host disease (GVHD), a potentially deadly side effect that occurs in approximately half of all transplant recipients.

GVHD occurs when transplanted donor immune cells, called T cells, attack the body’s tissues, especially the skin and intestinal tract. Although conventional treatments have targeted the donor T cells that cause GVHD, Holtan observed that even the strongest therapies were not making the majority of patients better. So she began to pursue a different approach—enhancing immune tolerance and wound healing processes.

“All of the immunosuppression we could possibly give wasn’t having an effect in patients with refractory GVHD,” she says. “I had to stop and think that maybe the reason for drug failure had nothing to do with our treatments, but something to do with the body’s ability to heal after injury.”

Pregnancy—“a temporary transplant situation”

Holtan’s interest in discovering new ways to stop GVHD continued for many years, but it wasn’t until she was pregnant with her first child as a fellow at Mayo Clinic that she had an “aha” moment that changed the trajectory of her work.

“When you’re pregnant, you have a sort of temporary transplant situation, without profound suppression of the immune system. You can still fight infections. I wondered—what about pregnancy keeps the body healthy and prevents it from rejecting a growing baby, and how can that be translated to overcome the complications of transplant?”

So Holtan searched for parallels between pregnancy and GVHD. Her most striking finding was that the presence of a protein called epidermal growth factor (EGF) was significantly higher than normal in pregnant women and in transplant recipients who do not have GVHD.

“We found that EGF is 20 times higher than normal in pregnant women, even within the first few weeks of pregnancy,” says Holtan. “We also found a similar phenomenon with our transplant patients—that a high level of EGF is associated with a successful transplant free of GVHD.”

Taking it a step further

Last year, Holtan and her team at the U built on her initial discovery by studying blood samples from patients with GVHD and confirming very low levels of EGF in patients with severe GVHD who did not respond to standard treatments.

Thanks to Masonic support, they are now taking this work a step further by studying biopsies from hundreds of patients both with and without GVHD to see if EGF and other proteins relevant to healing are present in human tissue. They expect to have results from this pilot study by summer 2017.

If successful, Holtan’s work could be game-changing for cancer patients who receive blood and marrow transplants. One result that Holtan sees in the not-so-distant-future is a test that can detect GVHD at its earliest stage.

She also sees significant potential for therapies that could cure GVHD by promoting immune tolerance and improving tissue repair processes using EGF or other key proteins. For example, her team recently launched a first-of-its-kind study on the impact of Pregnyl, an inexpensive hormone supplement that supports immune tolerance and contains high levels of EGF, in patients with GVHD. (To learn more, visit clinicaltrials.gov.)

Masonic support is “absolutely everything”

Holtan will be the first to say that much of her research is “outside of the box” and not as easy to fund as more established ideas. This has made support from the Minnesota Masons all the more vital to her team’s success.

“Receiving Masonic support is absolutely everything. They were willing to take a chance on research that is developmentally in very early stages,” Holtan says. “We’re grateful for the opportunity to move these projects forward. The reality is that we are beginning to make a real impact in patient lives right now with these studies, and that is very motivating.”