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Honoring the Legacy of E. Donnall Thomas

December 13, 2022

Dr. E. Donnall Thomas’ pioneering work in bone marrow transplantation cultivated a newfound appreciation for the complex and nuanced underpinning of the human immune system, as well as the complications that can arise from the transfer of immune cells from one person to another, including the debilitating consequences of graft-versus-host disease (GVHD). As the field of bone marrow transplantation has evolved, the historical and scientific steps forward have been dependent on our understanding of ways to mitigate GVHD risk. Apropos to the spirit of ingenuity cultivated by the “father of bone marrow transplantation,” this year’s E. Donnall Thomas Lecture and Prize was bestowed upon Dr. Bruce Blazar from the University of Minnesota, who has focused his career on better understanding the biology of GVHD and finding strategies to combat this disorder.

In his lecture aptly titled “The Long and Winding Road to Clinically Effective Graft-Versus-Host-Disease Therapeutics,” Dr. Blazar elegantly reviewed the current state-of-affairs in GVHD management as well as the incremental steps forward over the past 60 years as scientists and clinicians have tried to better understand the disorder. With dedicated inquiry and investigation, the medical community has made enormous progress from the early days of transplantation when GVHD was almost universally fatal. Just five years ago, there were no FDA-approved therapies to treat GVHD, and yet remarkably, from 2017 to 2021, there have been four effective drugs approved by the U.S. Food and Drug Administration (FDA) for GVHD.

While the number of failed therapies for GVHD far exceeds the number of approved therapies and the disease continues to pose challenges despite the availability of new therapies, the path toward a more hopeful tomorrow is becoming clearer. The successes and failures of clinical and research endeavors in the GVHD space have led to important advances in the knowledge of human leukocyte antigens (HLAs), which have aided clinicians in appropriate donor selection for transplantation. Moreover, attempts to prevent GVHD have led to the use of less toxic conditioning regimens, as well as prophylactic immunosuppression in the peri-transplant period. Ultimately, the key in ensuring a successful transplant is unleashing the power of T-cells in a manner that achieves a graft-versus-leukemia effect while preventing the T-cells from attacking host tissue and leading to GVHD. Like Goldilocks searching for the perfect bowl of porridge, it is all about striking a careful medium between two extremes.

As Dr. Blazar explained in detail, multiple therapeutics harnessing unique mechanisms of action have been shown to be effective in both acute and chronic GVHD treatment and prevention. Recently, the CTLA-4 antibody abatacept received FDA approval for the prevention of acute GVHD in combination with a calcineurin inhibitor and methotrexate. Abatacept induces immunosuppression by blocking T-cell signaling through interference with the CD28 and CTLA-4 costimulatory axis.

For chronic GVHD, which, unlike acute GVHD, has very similar  biology to an autoimmune disease with chronic fibrosis and inflammation, new therapeutics that interfere with inflammatory signaling have been introduced. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, has been shown to be effective at mitigating inflammation and disrupting B-cell–mediated anti-host antibody production. In addition, belumosudil, a selective rho-associated coiled-coil-containing protein kinase-2 (ROCK2) inhibitor that increases regulatory T-cells and decreases Th17 cells, is approved for the treatment of chronic GVHD after failure of at least two prior lines of systemic therapy. Lastly, in the areas of both acute and chronic GVHD, ruxolitinib, which inhibits the JAK-STAT signaling pathway, has shown remarkable efficacy by decreasing tissue inflammation and immune cell activation.

Clearly, the field of GVHD has come a long way beyond steroids. Building upon the legacy of Dr. E. Donnall Thomas, clinical investigators and basic scientists have forged a new path forward in this disease, which makes the long and winding road toward a future free of GVHD possible.

Dr. Hermel indicated no relevant conflicts of interest.

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