Hole in one: CD137-ADC eliminates GVHD Free

In this issue of Blood, Gerdemann et al¹ describe a promising new immunotherapeutic approach, showing that a single dose of CD137 antibody–drug conjugate can prevent acute graft-versus-host disease (GVHD) while preserving immune reconstitution in a nonhuman primate (NHP) model of stem cell transplantation. Although still in preclinical development, these findings support the potential for translation to highly needed human therapy.

GVHD remains one of the most severe complications of allogeneic hematopoietic stem cell transplantation (HCT). Despite advances in supportive care, conventional prophylactic regimens often rely on prolonged immunosuppression, which can delay immune reconstitution and increase both the risk of infections and relapse. In a compelling and innovative preclinical study, Gerdemann et al introduce a targeted strategy that could redefine acute GVHD prevention: a single, potent dose of a CD137-targeting antibody–drug conjugate (CD137-ADC) administered on the day of transplant.

This first-in-class immunotherapeutic strategy is built on a deceptively simple concept: to catch activated, alloreactive T cells in the act, and eliminate them before they become pathogenic. CD137 (also known as 4-1BB) is rapidly upregulated and colocalized at the immunological synapses upon T-cell activation,² making it an attractive early marker of alloreactivity in response to a defined antigenic trigger. The ADC developed by Gerdemann et al couples a CD137 targeting antibody, cross-reactive in humans and NHPs, to a transcription-inhibiting cytotoxic payload, α-amanitin, enabling selective deletion of activated and transcriptionally active cells.

The authors evaluated this strategy across models of increasing immunologic complexity, including a rigorously validated NHP model of major histocompatibility complex–haploidentical transplantation. The results were striking: animals treated with CD137-ADC exhibited markedly reduced clinical and histopathological features of GVHD, improved survival, and, notably, no need for additional immunosuppressive therapy. Posttreatment immune reconstitution revealed more than just GVHD-free survival: a diverse T-cell repertoire enriched in regulatory and memory subsets emerged, indicative of a rebalanced and restrained immune landscape (see figure).

Yet, this promising strategy is not without caveats. The selective elimination of activated T cells appears to create a vulnerability: an increased risk of reactivation of rhesus lymphocryptovirus (rhLCV), the NHP equivalent of Epstein-Barr virus (EBV). Of 6 treated animals, 5 developed significant rhLCV viremia, with some showing signs of end-organ manifestations. Notably, this viral reactivation coincided with the emergence of follicular helper T cells and interferon-signature memory subsets, populations not typically associated with GVHD, but which may contribute to a permissive environment for viral escape. Fortunately, this reactivation was responsive to rituximab, suggesting that preemptive antiviral strategies could be codeveloped alongside CD137-ADC use in humans.

In-depth immune profiling with flow cytometry and single-cell RNA sequencing allowed the authors to dissect not only the efficacy of CD137-ADC but also the characteristics of immune reconstitution that followed from the remaining cells. Their findings underscore a critical immunological insight: not all T-cell subsets equally contribute to GVHD, and some, particularly programmed death-1 (PD-1)^–OX40⁺ memory cells and forkhead box protein P3 (FOXP3)⁺ regulatory T cells, may support tolerance rather than inflammation. Looking at the viral reactivation risk, raises the possibility that, if by preserving these subsets, CD137-ADC strikes the optimal balance between preventing GVHD and allowing effective immune reconstitution, thereby potentially preserving antileukemic (graft-versus-leukemia [GVL]) effects.^3,4 Although the NHP model cannot directly assess antileukemic activity, in vitro cytotoxicity assays demonstrated that CD137-ADC–exposed T cells retained antilymphoma activity at high effector-to-target ratios, with reduced function at lower ratios. The impact on GVL must be carefully evaluated in human clinical studies, particularly if CD137-ADC is used prophylactically. However, the short half-life (∼2 days) may allow for immune recovery when the relapse risk typically emerges. This approach would offer many potential advantages over conventional, prolonged immunosuppressive regimens.

A single-dose intervention strategy aligns with the clinical aim to simplify posttransplant care, reduce toxicity, and improve early immune fitness. The rapid clearance of CD137-ADC from the circulation within 2 weeks makes it especially appealing, potentially avoiding the long-term complications associated with sustained immunosuppression. However, the study findings emphasize the need for careful design of future human trials, particularly with regards to monitoring and managing opportunistic infections. Although cotreatment with rituximab, as proposed by the authors, may mitigate the risk of EBV reactivation, it offers no protection against other viral threats, underscoring the importance of comprehensive infectious disease surveillance during clinical translation.

Gerdemann et al are not merely introducing a new drug, they are proposing a paradigm shift. Rather than broadly suppressing the immune system, their approach targets and eliminates the most problematic cells at the peak of their activation, allowing space for a more functional and tolerogenic system to emerge. This approach offers a streamlined alternative to complex graft engineering or posttransplant donor lymphocyte infusions for immune restoration.⁵ If these results do translate to humans, CD137-ADC could redefine GVHD prevention, and may also open avenues to identifying even more refined targets in the future. At present, CD137 seems to be one of the most rational and selective targets for early posttransplant allogeneic T-cell depletion given its transient and activation-specific expression, its favorable internalization properties for ADC delivery,⁶ and its ability to spare important naïve and memory subsets.

In an era, in which precision immunotherapy is transforming oncology and autoimmune diseases, this study takes a major step toward bringing those principles to the field of transplantation. By selectively targeting the right cells, at the right time, with a potent yet transient agent, the authors pave the way for safer, more effective HCT, potentially extending its benefits to a broader group of patients.

Conflict-of-interest disclosure: The authors declare no competing financial interests.