To successfully rebuild the immune system and prevent relapse after a stem cell transplant, it is necessary to have the right balance of two types of T cells – effector T cells and regulatory T cells.

In GVHD, effector T cells become hyperactive. Without enough regulatory T cells present in the patient’s developing immune system, the activated effector T cells relentlessly work against their healthy tissues.

In many cases, the drugs currently available to prevent and treat GVHD are often ineffective because they suppress the immune system too broadly. The treatments eliminate the bad, overactive effector T cells, but they can also suppress the good, regulatory T cells.

“We’re getting better at controlling effector T cells, but it’s a very high bar to find a therapeutic strategy that both can reign in the effector T cells and allow regulatory T cells to flourish,” said Dr. Leslie Kean, associate director of the Ben Towne Center for Childhood Cancer Research at Seattle Children’s Research Institute. “Achieving the right balance remains one of the great mysteries of preventing GVHD after transplant.”

Building on a decade of work dedicated to finding the right combination of therapies to prevent GVHD, promising new research by Kean and a research scientist in her lab, Dr. Victor Tkachev, suggests this balancing act is within reach.

In their research published in the journal Science Translational Medicine, Kean and Tkachev combined one drug already available to transplant patients, sirolimus, with an experimental, novel human antibody therapy that targets a key pathway in T cell activation known as the OX40:OX40L pathway. Kymab, a biopharmaceutical company, is currently testing the antibody, known as KY1005, in its first-in-human trials.

The drugs work synergistically to prevent GVHD by blocking two different pathways important to T cells. Sirolimus works as an inhibitor of the mTOR pathway, slowing the production of a protein that stimulates effector T cells while stabilizing the regulatory T cells. However, sirolimus alone does not adequately control effector T-cell activation. It’s for this reason the addition of KY1005 is critical, as it prevents the continued attack of healthy tissue by the effector T cells.

“Here, we show how KY1005 silences the signaling that activates effector T cells while leaving regulatory T-cell function untouched,” said Tkachev. “Alone, neither drug could completely orchestrate this delicate balance, but when we tested them together, they proved highly effective in this difficult task.”

The preclinical studies conducted by Kean and Tkachev found that KY1005 and sirolimus prevented GVHD by simultaneously reducing damaging effector T-cell activity and preserving regulatory T-cell populations. Furthermore, the combination provided a considerable survival benefit in animal models.

“In all my years, I’ve never seen a combination as successful at controlling GVHD as this,” said Kean. “Our findings suggest this combination may represent a new way for us to tune the immune system after transplant.”

Kean said a clinical trial to test the sirolimus-KY1005 combination in patients is in the early planning stages with Kymab and Seattle Children’s. Such a therapeutic option, if successful in patients, would offer an attractive strategy to prevent GVHD.