Image from PLOS ONE
Micrograph showing GVHD
An investigational JAK1/2 inhibitor can fight graft-versus-host disease (GVHD), according to preclinical research published in Leukemia.
The inhibitor, baricitinib, reduced GVHD in mice while preserving T-cell expansion and the graft-versus-leukemia (GVL) effect.
Baricitinib proved more effective than ruxolitinib for the treatment and prevention of GVHD and enabled 100% survival in a mouse model of severe GVHD.
“We were surprised to achieve 100% survival of mice with the most severe model of graft-versus-host disease,” said study author Jaebok Choi, PhD, of the Washington University School of Medicine in St. Louis, Missouri.
“We are now studying the multi-pronged ways this drug behaves in an effort to develop an even better version for eventual use in clinical trials.”
For the current study, Dr Choi and his colleagues tested baricitinib and ruxolitinib in murine recipients of allogeneic hematopoietic stem cell transplants (allo-HSCTs). Mice received either drug for 31 days post-HSCT.
Mice treated with baricitinib had a significant reduction in intestinal GVHD compared to both ruxolitinib recipients and vehicle-treated controls (P=0.037).
In addition, 100% of baricitinib recipients were still alive at 60 days after HSCT, compared to about 60% of ruxolitinib recipients (P=0.0025) and almost none of the vehicle-treated controls.
The researchers found that baricitinib recipients had significantly better blood cell count recovery than control mice. Baricitinib recipients also had full donor chimerism and significantly higher percentages of donor bone marrow-derived B and T cells.
Furthermore, baricitinib recipients had higher levels of donor-derived regulatory T cells (Tregs) compared to vehicle- or ruxolitinib-treated mice.
However, the researchers noted that baricitinib recipients had a survival rate of about 70% even in the absence of donor Tregs. The team said this suggests baricitinib fights GVHD independently of the enhanced expansion of Tregs.
Further investigation revealed that baricitinib decreases helper T-cell 1 and 2 differentiation and reduces the expression of MHC II, CD80/86, and PD-L1 on allogeneic antigen-presenting cells.
The researchers also found that baricitinib could reverse ongoing GVHD. The team withheld baricitinib until mice developed GVHD, then tested the drug at doses of 200 μg and 400 μg per day.
Both doses reduced clinical GVHD scores and enabled 100% overall survival rates.
Finally, the researchers found that baricitinib “preserves and enhances” GVL effects. The team infused A20 cells and T-cell-depleted bone marrow cells into lethally irradiated mice, waited for the B-cell lymphoma to become established, and infused donor T cells.
The researchers found that baricitinib alone did not inhibit tumor growth, but it enhanced the GVL effects of donor T cells, significantly lowering the tumor burden.
“We don’t know yet exactly how this happens, but we’re working to understand it,” Dr Choi said. “We think at least part of the explanation is the drug strips the leukemia cells of their immune defenses, making them more vulnerable to attack by the donor T cells.”
“At the same time, the drug also stops the donor T cells from being able to make their way to important healthy tissues, such as the skin, liver, and gastrointestinal tract, where they often do the most damage.”