An important aspect of allogeneic hematopoietic stem cell transplantation (alloHCT) that has been the focus for many in the field over the last several decades is the separation of two closely linked post-transplant immunologic phenomena: graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect. Transplantation is an important curative-intent therapy — and indeed, the only pathway to disease eradication for many — but how can we maximize our chances of achieving our intended cure while also minimizing the potentially devastating consequences of allogeneic responses against host tissues? How can we turn down the volume on the immune system enough to prevent or definitively treat GVHD but retain the protective GVL effects that are so important for long-term disease control? Furthermore, in addition to ensuring that the patient remains free of leukemia and GVHD, how do we ensure immune recovery robust enough to keep opportunistic infections at bay? In their recent study published in Science Translational Medicine, Mariano Prado-Acosta, PhD, and colleagues described a novel targeting strategy that may help to answer these questions.1
The authors investigated the role of receptor-interacting protein kinase 1 (RIP1) inhibition using mouse models of alloHCT. RIP1 (also referred to as RIPK1) regulates inflammatory cell death and is a key part of the signaling pathway downstream of tumor necrosis factor (TNF). TNF was identified as an important pathogenic cytokine in mouse models of GVHD more than 20 years ago,2-4 and early clinical trials of inhibition-based GVHD therapy showed promise5 ; however, it has not become a mainstay of current GVHD treatment.
In the study by Dr. Prado-Acosta and colleagues, more precise downstream inhibition of the TNF signaling pathway with an RIP1 inhibitor (GNE684) resulted in less acute GVHD in two separate transplant models. The authors reported that the mechanism of protection was largely due to the prevention of apoptosis in intestinal stem cells. Moreover, they confirmed that the anti-inflammatory effect of RIP1 inhibition did not increase relapse rates, again using several mouse models of leukemic relapse after alloHCT. Intriguingly, in a separate study also published in 2023, Xiaoliang Yu, PhD, and colleagues also studied the role of RIP1 inhibition in GVHD. Using a different small-molecule inhibitor (Zharp1-211), they demonstrated similar benefits, particularly within the intestinal epithelial cell compartment.6
In Brief
The work of Dr. Prado-Acosta’s team, along with the study by Dr. Yu and colleagues, highlights the potential of novel small-molecule RIP1 inhibitors in the post-transplant setting. These agents appear to protect the gastrointestinal tract from apoptotic damage and — critically — do not seem to impair anti-leukemic activity.
Competing Interests
Dr. Markey indicated no relevant conflicts of interest.
