Research at CCCZ: Understanding Blood Cancers, Developing Immunotherapies, Optimizing Treatments

Schimmer et al., Blood, 2026

Individuals with alterations in the ERCC6L2 gene can develop a rare form of bone marrow failure, in which the marrow no longer produces sufficient blood cells. At the same time, affected individuals have an increased risk of developing myeloid leukemia later in life.

Notably, these patients frequently acquire additional alterations in the TP53 gene. TP53 is a key tumor suppressor gene that normally helps stop or eliminate cells with severe damage.

The study explains why TP53 alterations are so common in this condition. When ERCC6L2 is deficient, hematopoietic stem and progenitor cells experience stress. They accumulate DNA damage, show impaired growth, and are less able to fulfill their function in the bone marrow. If TP53 is also inactivated, these cells can temporarily regain their growth capacity—acting as a form of genetic “rescue” of blood formation.

However, this rescue comes at a cost: DNA damage persists. Without the protective function of TP53, genetically unstable cells can continue to proliferate, increasing the long-term risk of leukemic transformation.

This work illustrates how a short-term beneficial genetic change can contribute to cancer development over time. It provides a striking example of how closely bone marrow failure, genetic adaptation, and leukemia risk are linked.

The study was prominently featured in Blood as a Plenary Paper, accompanied by a commentary, cover placement, and a podcast explaining the findings.

Publication: Blood (2026) 147 (15)

Podcast featuring Steffen Böttcher: Blood Podcast by American Society of Hematology

Kaiser et al., Leukemia, 2026

Systemic mastocytosis is a rare disease characterized by the accumulation of abnormal mast cells in various organs. Advanced forms can be severe and remain difficult to treat despite new targeted therapies.

The research team investigated a novel immunotherapeutic approach: CAR T cells targeting the surface molecule CD117 (KIT), which is highly expressed on mast cells and plays a central role in this disease.

In preclinical models, CD117 CAR T cells effectively targeted multiple mast cell–based disease models, including mast cell lines, patient-derived mast cells, and malignant bone marrow cells from patients with systemic mastocytosis. In mouse models, repeated CAR T-cell administration inhibited mast cell expansion.

The study suggests that CAR T-cell therapies could be further developed for advanced systemic mastocytosis, offering new perspectives for patients who do not respond adequately to current treatments.

Publication: Leukemia (2026)

Volta et al., Molecular Cancer Therapeutics, 2026

Many modern immunotherapies target a single antigen on cancer cells. While effective, this approach has limitations: tumor cells can change, lose target antigens, or express multiple markers simultaneously. This is particularly challenging in acute myeloid leukemia, where many targets are also present on healthy hematopoietic cells.

To address this, researchers developed a modular system consisting of a T-cell engager that activates T cells and interchangeable adapter molecules that bind to different target structures on leukemia cells. Targets studied included CD33 and CD117.

The key advantage is flexibility: T-cell activation is not fixed to a single tumor antigen but can be redirected via adapters to different targets.

In preclinical models, the system effectively eliminated leukemia cells and showed in vivo inhibition of leukemia growth comparable to related adaptor CAR T-cell approaches.

This work points to a potential next generation of immunotherapies—more flexible, controllable, and adaptable to tumor heterogeneity. Such platforms may ultimately enable safer and more personalized treatments.

Publication: Mol Cancer Ther 2026

A similar concept was previously demonstrated in adaptor CAR T-cell approaches: Leukemia (2024)

Hofstetter et al., Cancer Research Communications, 2026

T-cell engagers are engineered antibodies that bring T cells into direct contact with cancer cells by binding both a tumor antigen and CD3 on T cells, thereby triggering T-cell activation.

A limitation of conventional T-cell engagers is the lack of a second, costimulatory signal, which is important for a strong and sustained T-cell response. In contrast, modern CAR T cells incorporate such signals, for example via CD28 or 4-1BB.

The researchers addressed this in acute myeloid leukemia by combining a CD117×CD3 T-cell engager with a second bispecific antibody targeting CD33 and delivering a CD28-mediated costimulatory signal.

This creates a two-step activation mechanism: CD117 serves as the primary target, CD33 as the secondary signal. Strong T-cell activation occurs when both signals are present.

In preclinical studies, this approach led to enhanced T-cell activation, proliferation, cytokine release, and improved killing of AML cells. Dual targeting also improved specificity by preferentially eliminating cells expressing both CD117 and CD33.

The study demonstrates how T-cell engagers can be rationally enhanced to improve efficacy while increasing targeting precision.

Publication: Cancer Research Communications (2026) 6 (4)

Koch et al., Frontiers in Immunology, 2026

Chronic graft-versus-host disease (cGVHD) can occur after allogeneic stem cell transplantation, when donor immune cells attack the patient’s healthy tissues. The condition can affect multiple organs and significantly impair quality of life.

This study analyzed patients with steroid-refractory or steroid-dependent cGVHD, comparing extracorporeal photopheresis alone with a combination of photopheresis and the JAK inhibitor ruxolitinib.

The combination showed higher and faster response rates in this retrospective analysis. Importantly, it also had a steroid-sparing effect: after 12 months, significantly more patients in the combination group were able to discontinue corticosteroids completely.

Given the substantial long-term side effects of corticosteroids, treatments that act faster and reduce steroid exposure can make a meaningful difference for patients. This study provides valuable real-world evidence on effective combination strategies.

Publication: Front. Immunol., 22 April 2026