Allogeneic stem cell transplantation (allo-SCT) is undertaken with a singular goal: to cure leukemia by replacing a diseased immune system with that of a healthy donor, capable of recognizing and eliminating malignant cells. When successful, this graft-versus-leukemia (GvL) effect allows the donor immune system to remain vigilant, providing long-term disease control by continually keeping leukemia in check.
Yet relapse remains a persistent challenge. Despite successful engraftment and initial disease clearance, approximately one-third of patients who undergo allo-SCT experience relapse after transplant[4]. Once relapse occurs, treatment options are limited, and survival is often measured in months rather than years.
Critically, post-transplant relapse does not usually reflect an absence of donor immunity. Donor immune cells remain present, and leukemia antigens persist. What changes instead is the immune context: immune activation thresholds rise, innate sensing weakens, and the signals required to sustain effective GvL gradually fade. In this setting, relapse is better understood as a state of immune suppression rather than immune failure.
LEUMUNA™ is an oral immune checkpoint modulator being developed specifically to address this challenge. Rather than targeting leukemia cells directly, it is designed to re-engage donor-derived immune cells, enabling them to once again recognize and eliminate malignant cells through a natural process known as graft-versus-leukemia (GvL) effect. In doing so, LEUMUNA positions the donor immune system itself as the therapy, shifting the paradigm from salvage treatment toward immune reactivation, long-term control, and the potential for deeper, more durable remission[1].
Why Relapse Occurs after Allo-SCT
“I still remember a young man — he was just 26 — who was brought in by ambulance to Frankfurt University Hospital while I was working there as a hemato-oncologist. He was severely emaciated and suffering from pneumonia. When the initial blood tests came back, his blood was essentially white. We diagnosed acute leukemia immediately. His condition was so critical that we had to place him in an induced coma to begin high-dose chemotherapy, alongside intensive antibiotics to treat the pneumonia.
He had seen his GP several times with symptoms that appeared to be nothing more than a persistent cold. Leukemia often begins with non-specific symptoms, can affect young adults and children, and may progress quickly, making timely investigation of unresolved symptoms essential”.
Thomas Mehrling, MD, PhD, CEO of Helix BioPharma
Allo-SCT replaces the patient’s immune system with donor cells that are naturally primed to recognize and attack leukemia. Unlike the patient’s innate immune system, donor immune cells have not adapted to the presence of leukemia and can more readily identify leukemic cells as abnormal. This dynamic, known as the GvL effect, is essential to achieving remission.
However, relapse after transplant often begins with immune escape. Leukemia cells can modify the pathways that allow donor immune recognition, reducing antigen presentation, suppressing interferon-gamma responses, and weakening T-cell signaling. As these changes accumulate, donor immunity may lose the strength and precision it needs to maintain long-term control, allowing relapse to progress quietly[1, 2].
Research has shown that patterns of immune recovery after transplant strongly influence relapse risk. Donor CD8+ effector and memory T-cell function, CD4+ naïve T-cell balance, and T-cell receptor (TCR) clonality between 30 and 60 days post-transplant correlate strongly with long-term outcomes. Together, these findings support a future in which restoring donor immune function, at the right time and in the right way, may be a key factor in preventing relapse[1, 3].
When relapse occurs after allo-SCT, treatment options are limited. Available interventions, such as donor lymphocyte infusions, additional chemotherapy, or experimental therapies, are often constrained by toxicity, feasibility, or limited durability of response. As a result, outcomes in post-transplant relapse remain poor, highlighting the unmet need for approaches that address underlying immune dysfunction.
What LEUMUNA is designed to do
LEUMUNA is an investigational, orally administered small-molecule therapy designed to restore immune control in post-transplant relapse by reactivating donor-derived immune function, rather than by directly targeting leukemia cells. Its development reflects the understanding that relapse after allo-SCT usually occurs despite the continued presence of donor immune cells, when immune signaling and coordination within the donor immune system have become suppressed.
Mechanistically, LEUMUNA (ulodesine hemiglutarate) inhibits purine nucleoside phosphorylase (PNP), an enzyme that normally breaks down guanine nucleosides within immune cells. By inhibiting PNP, LEUMUNA leads to an increase in intracellular guanosine and related molecules, which serve as necessary partners for Toll-like receptor 7 (TLR7), an innate signaling receptor expressed on donor-derived immune cells. These nucleosides do not trigger TLR7 on their own, but they enable the receptor to respond more robustly to endogenous RNA derived from leukemia cells and surrounding tissues as part of normal cellular turnover. In effect, LEUMUNA releases a metabolic checkpoint that had been suppressing TLR7-dependent signaling, allowing donor immunity to re-engage the GvL response[5].
This activation engages downstream pathways, including MYD88, IRF5, and NF-κB, that promote cytokine signaling and coordinated activation of donor T cells and germinal-center B cells. These immune cells carry out the GvL effect by recognizing, targeting, and eliminating leukemia cells, while helping sustain immune pressure over time.
By focusing on recalibrating donor immune signaling rather than escalating treatment intensity, LEUMUNA represents a strategy aimed at restoring durable immune control in a setting where donor immunity is already in place but no longer fully effective. This targeted restoration distinguishes LEUMUNA from systemic immune stimulants or checkpoint inhibitors, which can overwhelm immune regulation and increase the risk of graft-versus-host disease (GvHD). Because it is taken orally, LEUMUNA may offer a more practical and less hospital-dependent approach than donor lymphocyte infusions, repeated chemotherapy cycles, or cell-based immunotherapies. The therapy also carries US FDA Orphan Drug Designation for post-transplant relapse, reflecting both the rarity and severity of this condition[1, 2]. LEUMUNA has demonstrated significant survival benefits in mouse models of B Cell acute leukemia relapse, achieved by indirectly activating T cells and triggering GvL effect[X]. Further supporting its mechanism as an immune checkpoint modulator is the precedent set by forodesine hydrochloride, a pharmacologically analogous PNP inhibitor. Forodesine has shown early clinical efficacy in hematological malignancies, including two patients who achieved complete remission after relapsing with T-cell acute lymphoblastic leukemia following allo-SCT[Y]. One of these patients, a three-year-old little girl, became a symbol of hope in a widely shared case study on YouTube titled “When a Drug Becomes a Child’s Last Hope for T-Cell Leukemia”. Forodesine was ultimately approved in Japan for peripheral T-cell lymphoma under the trade name Mundesine™, through broader clinical development was limited by a complex manufacturing process and subsequent patent expiry.
LEUMUNA advances the potential first demonstrated by forodesine, with an improved synthesis and scalability. Its predecessor compound, ulodesine (BCX-4208), has a well-characterized safety profile from clinical studies in over 500 patients and volunteers, providing a strong foundation for LEUMUNA’s development as a targeted immune-modulating therapy[Z].
A Fit Within Evolving Transplant Science
Over the past decade, the field of allogeneic stem cell transplantation has shifted from a primary focus on engraftment toward a more nuanced effort to shape post-transplant immunity. Increasingly, long-term success is understood to depend on sustaining GvL activity while limiting GvHD. Strategies such as refined conditioning regimens, post-transplant cyclophosphamide, and selective immunomodulation reflect this evolution, emphasizing immune balance and timing rather than maximal immune activation.
LEUMUNA aligns with this direction by intervening after engraftment to restore suppressed immune signaling within the donor immune system. Rather than adding new immune cells or broadly stimulating immunity, this approach is designed to recalibrate immune responsiveness, supporting coordinated donor immune activity against relapse while preserving regulatory control.
Current treatments for post-transplant relapse, including donor lymphocyte infusions and hypomethylating agents, can reintroduce immune pressure but are often constrained by toxicity, feasibility, or limited durability of response in a physically fragile population. Off-label use of checkpoint inhibitors has demonstrated immune activity but carries significant risk in the transplant setting due to non-selective immune activation. In contrast, LEUMUNA™ represents a move toward greater precision and practicality: an orally administered immune-modulating therapy developed specifically for post-transplant relapse.
This mechanism also aligns with emerging efforts to address relapse earlier. As measurable residual disease (MRD) testing becomes increasingly sensitive, clinicians are identifying molecular relapse well before clinical progression. In this context, therapies that can restore immune surveillance without excessive toxicity may be deployed pre-emptively. If positioned appropriately, LEUMUNA™ has the potential to evolve from a salvage therapy into a maintenance-style approach, supporting immune control during periods when relapse remains biologically reversible.
The Future of Post-Transplant Immune Activation
Looking ahead, the long-term potential of LEUMUNA may lie in its integration with emerging immune profiling tools, including MRD assays, TCR analytics, and immune phenotyping. Together, these technologies could help inform when and how immune recalibration is most effective, enabling treatment strategies that are guided by immune state rather than disease burden alone.
If these principles translate into clinical benefit, LEUMUNA may help reframe relapse after transplant, not as a failure of transplantation, but as a window of opportunity to restore immune control. By focusing on recalibrating donor immunity rather than escalating treatment intensity, this approach reflects a broader shift in how post-transplant release is understood and addressed.
At Helix BioPharma, we are committed to advancing therapies that reflect this evolving biology. Our aim is to expand options for patients facing post-transplant relapse and to help move forward the field toward a future in which it can be anticipated, intercepted, and managed through informed immune restoration.
References:
1. Burk AC, Apostolova P. Metabolic instruction of the graft-versus-leukemia immunity. Front Immunol. 2024 Mar 4;15:1347492. doi: 10.3389/fimmu.2024.1347492. PMID: 38500877; PMCID: PMC10944922.
2. Sterling C, Webster J. Harnessing the immune system after allogeneic stem cell transplant in acute myeloid leukemia. Am J Hematol. 2020;95(5):529-547. doi:10.1002/ajh.25750
3. Dai W, Hao S, Wu L, Zhao X, Dong F, Wang L, Jiang E, Cheng T. Early immune reconstitution and relapse-related characteristics in acute myeloid leukemia patients after transplantation. Blood. 2024;144(Suppl 1):7347. doi:10.1182/blood-2024-209275
4. Eléonore Kaphan, François Bettega, Edouard Forcade, et al; Late relapse after hematopoietic stem cell transplantation for acute leukemia: a retrospective study by SFGM-TC; Transplantation and Cellular Therapy; Volume 29, Issue 6, June 2023.
5. Evan R. Abt, Khalid Rashid, Thuc M. Le, Suwen Li, Hailey R. Lee, et al; Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-associated autoimmunity; reviewed from https://www.jci.org/articles/view/160852/pdf
X. See unpublished data on p. 17 of our non-confidential deck: https://www.helixbiopharma.com/wp-content/uploads/2025/06/Helix-Public-Deck_June-2025.pdf
Y. https://www.sciencedirect.com/science/article/abs/pii/S0093775407002242?via%3Dihub