Relapses in acute myeloid leukemia are caused by malignant cells that resist standard treatments. Synthetic cytokine approaches in development target inflammatory cell death pathways and suppress leukemic cells while preserving healthy hematopoiesis.
acute myeloid leukemia (AML) is an aggressive cancer of the blood and bone marrow characterized by rapid proliferation of immature bone marrow cells that interferes with normal blood formation. Standard treatment usually includes intensive chemotherapy, often followed by stem cell transplantation in eligible patients, with the aim of achieving complete remission.
Despite the initial response, relapse remains common. Disease recurrence is primarily caused by leukemic stem cells. Leukemia stem cells are a small population of malignant cells that can survive front-line treatments and later reproduce the disease. These cells are inherently resistant to many cytotoxic agents and are associated with poor long-term outcomes. Therefore, prevention of relapse remains one of the central challenges of AML research and drug development.
in Cycuria Therapeuticstherapeutic strategies are being developed that focus on biological differences between leukemic and healthy hematopoietic cells rather than non-selective cytotoxicity or mutation-specific targets. This approach takes advantage of inflammatory signaling and programmed cell death pathways that are differentially regulated in malignant cells. It uses a synthetic cytokine based on lymphotoxin alpha. This cytokine has shown selective activity against leukemic stem and progenitor cells in preclinical models while largely preserving normal hematopoiesis.
This study builds on more than 20 years of research into cell death and inflammation led by Dr. Philip Jost. In parallel with my clinical responsibilities leading the Clinical Department of Oncology at the Medical University of Graz, I have spent over 20 years researching how inflammatory pathways shape cancer development and progression. His long-standing interest in cell death biology led him to co-found Cycuria Therapeutics with CEO Dr. Nisit Khandelwal. Drawing on his experience as a hematologist and oncologist, Dr. Jost currently leads the company’s scientific team with a focus on acute myeloid leukemia and resistance mechanisms.
Rediscovery of lymphotoxin alpha in AML
Lymphotoxin alpha is a cytokine belonging to the tumor necrosis factor (TNF) superfamily and is well known for its ability to induce inflammation. However, its role in cancer biology has historically been complex and context-dependent.
We tested a variety of cytokines and confirmed that lymphotoxin alpha plays a potent leukemia-suppressive role using primary patient samples and a variety of mouse model systems.
Dr. Jost’s interest in lymphotoxin alpha stemmed from an earlier study published in 2016 in which his group demonstrated that the kinase RIPK3 inhibits myeloid leukemia. This discovery prompted a search for upstream signals that can activate RIPK3-dependent cell death in malignant cells.
The research team used primary patient-derived samples in parallel with multiple mouse model systems to systematically assess inflammatory cytokines and identify potential candidates that trigger this pathway.
Dr. Jost said, “We tested a variety of cytokines and using primary patient samples and a variety of mouse model systems, confirmed that lymphotoxin alpha plays a potent leukemia-suppressive role.”
Lymphotoxin alpha exhibited a markedly different toxicity profile compared to TNF, a closely related cytokine that has long been limited by systemic side effects.
“Importantly, we found that lymphotoxin alpha differs from TNF in that it induces substantially lower systemic toxicity when administered to laboratory mice,” Dr. Jost said.
These findings provided the biological basis for the development of CUR-101, a synthetic biologic designed to exploit the tumor-suppressive properties of lymphotoxin alpha.
Limitations of current AML treatments
Despite significant advances in therapy, treatment options for acute myeloid leukemia remain limited by toxicity, limited coverage, and high recurrence rates.
Current treatments for AML rely heavily on suppressing malignant AML clones with chemotherapy and on drugs targeting specific genetic subgroups of AML.
“Current AML treatments rely heavily on suppressing malignant AML clones with chemotherapy and on drugs that target specific genetic subgroups of AML,” Dr. Jost said.
Although young, healthy patients may proceed to stem cell transplantation, many older or frail individuals cannot tolerate intensive treatment regimens. Even among those who have relapsed, relapse remains common.
Dr. Jost added, “Despite intensive treatment schedules, recurrence rates are high, even in younger, fitter patients, and this is a major challenge with current treatment options.”
Targeted therapies have improved outcomes in defined molecular subgroups, but are only applicable to a minority of patients, leaving a substantial unmet need for broadly applicable and less toxic approaches.
Dual mechanism approach with CUR-101
CUR-101 represents a mechanistically distinct strategy. Rather than focusing solely on inhibiting proliferation or targeting individual mutations, we aim to reprogram leukemic cells by activating inflammatory cell death and forcing myeloid differentiation.
We showed that CUR-101, a synthetic biologic based on lymphotoxin alpha, potently induces cell death and myeloid differentiation in the leukemic progenitor compartment.
“We showed that CUR-101, a lymphotoxin alpha-based synthetic biologic, potently induces cell death and myeloid differentiation of the leukemic progenitor cell compartment.”
These two effects work in concert to slow disease progression, Dr. Jost said.
“Therefore, CUR-101 is able to suppress leukemia progression through two independent, but highly synergistic, molecular mechanisms.”
Importantly, this activity appears to be highly selective for malignant cells. Healthy hematopoietic cells and the surrounding bone marrow environment remain largely intact.
“Hematopoietic cells in healthy humans and even adjacent hematopoietic cells in the bone marrow of AML patients are largely unaffected by CUR-101.”
In some experimental settings, this compound appears to actively support normal blood formation.
“In fact, we even observed an improvement in the number of healthy hematopoietic progenitors and mature hematopoietic cells, indicating a beneficial effect of CUR-101 on healthy hematopoiesis.”
Harnessing the asymmetry of leukemia stem cell signaling
The selectivity of CUR-101 arises from differences in intracellular signaling capacity between malignant and healthy cells. Lymphotoxin alpha signals primarily through TNF receptor 1 and indirectly through TNF receptor 2.
Activation of both receptors leads to competition for the adapter protein TRAF2, which is required for prosurvival signaling. In leukemic cells, baseline TRAF2 levels are low, and this competition destabilizes survival signaling complexes.
“Intracellular competition for TRAF2 reduces the amount of TRAF2 available to TNFR1, resulting in failure to form a functional pro-survival signaling hub.”
Malignant cells are suppressed while healthy cells are simultaneously promoted by the same compound, providing an exceptional therapeutic area.
This failure causes RIPK3-dependent inflammatory cell death. In contrast, healthy hematopoietic cells contain sufficient TRAF2 to maintain survival signaling even in the presence of lymphotoxin alpha.
“Thus, while malignant cells are suppressed, healthy cells are simultaneously promoted by the same compound, providing an extraordinary therapeutic window.”
Preclinical evidence supporting development
Extensive preclinical studies have increased confidence in the therapeutic potential of CUR-101. Lymphotoxin α-based therapy resulted in durable disease control in both syngeneic and patient-derived xenograft models.
“We confirmed that lymphotoxin alpha achieved durable leukemia control in both syngeneic and patient-derived xenograft models, with disease suppression maintained for more than 300 days and no meaningful safety signals in animals.”
The compound has also been tested in a wide range of human AML primary bone marrow samples representing multiple genetic subtypes and ELN risk groups.
“We consistently observe strong induction of differentiation with a significant reduction in malignant progenitor cells. ex vivo Assay. ”
Together, these data provide a strong rationale to advance CUR-101 toward clinical evaluation.
Preparing for First-in-Human research
Cycuria is currently progressing toward GMP manufacturing and IND-enabling research planned for 2026. Key priorities include establishing a robust manufacturing process and completing GLP safety and toxicology studies.
We are planning a Phase I clinical trial to learn as much as possible from the first patients we treat.
“For us, that means perfecting a reliable GMP process so we can deliver a high-quality, clinical-grade product, and completing GLP safety and toxicology studies in non-human primates to clearly define the therapeutic scope.”
In parallel, the company is building a detailed pharmacokinetic and pharmacodynamic framework and expanding its biomarker program to support patient selection and early proof of mechanism.
“And, of course, we are planning a Phase I clinical trial so that we can learn as much as possible from the first patients we treat.”
durable disease control
Dr. Jost sees this strategy as a way to move beyond short-term remission toward sustained disease control.
“By focusing on leukemia stem cells, the cells responsible for relapse, and at the same time supporting the restoration of healthy hematopoiesis, we aim to go beyond simply inducing remission.”
If clinical results reflect preclinical findings, CUR-101 may represent a new class of AML treatment that combines durability and reduced toxicity.
“If the clinical data reflect what we have seen preclinically, I believe this approach has the potential to provide more durable, less toxic, and more personalized outcomes for AML patients who urgently need better options.”
meet an expert
Professor Philip J. Jost is the scientific founder and managing director of Cycuria. He is Full Professor of Clinical Oncology and Director of the Clinical Oncology Department and the University Department of Palliative Care at the Medical University of Graz, Austria. He is also Director of the Comprehensive Cancer Center at the Medical University of Graz.
Professor Jost is a board-certified hematologist and medical oncologist. He completed clinical and research training at the Technical University of Munich (Germany), Imperial College London (UK), and the Walter & Eliza Hall Institute of Medical Research in Melbourne (Australia).