Engineering shielded, bone marrow homing regulatory T cells for hypoplastic myelodysplastic neoplasms

Primary supervisor: Shahram Kordasti, King’s College London

Secondary supervisor: Sara Ghorashian, UCL

Project

Hypoplastic myelodysplastic neoplasms (hMDS) are a distinct subgroup of myelodysplastic neoplasms characterised by reduced bone marrow cellularity, ineffective haematopoiesis, cytopenias and a risk of progression to acute myeloid leukaemia. In this clinically important subset, autoreactive T cells and inflammatory cytokines damage residual haematopoietic stem and progenitor cells. Current approaches, including immunosuppressive therapy and allogeneic stem cell transplantation, have variable efficacy and are limited by toxicity, donor availability and patient fitness. There is therefore a need for targeted therapies that restore immune tolerance while protecting normal haematopoiesis.

Regulatory T cell (Treg) therapy is a promising way to suppress pathogenic immune responses without causing broad immunosuppression. Its effectiveness may, however, be restricted by apoptosis within the inflammatory marrow environment, insufficient persistence and poor localisation to the bone marrow. This project will develop next generation engineered human Tregs designed to overcome these barriers.

The student will build on a shielded Treg platform with resistance to FAS mediated apoptosis. Tregs will be further engineered with a hypoxia responsive gene circuit that induces CXCR4 expression within low oxygen environments, thereby promoting migration towards CXCL12 and selective retention in the bone marrow niche. An inducible IL-10 module will also be evaluated as a means of strengthening local immunoregulation and protecting residual haematopoiesis.

The project has three objectives. First, the student will construct and compare engineered Treg products incorporating FAS resistance, hypoxia responsive CXCR4 and inducible IL-10, individually and in rational combinations. Second, the products will be characterised under normoxic and hypoxic conditions using flow cytometry, molecular assays, apoptosis and stability measurements, migration assays, cytokine profiling and functional suppression assays. Third, lead candidates will be tested in patient derived hMDS assays and relevant preclinical models to determine whether they suppress pathogenic immune responses, preserve haematopoietic stem and progenitor cells and improve haematopoietic function. The work will define a lead cellular product and the biological evidence required for subsequent translational development which can also be used in other types of malignancies such as myelofibrosis.

Candidate background

This project would suit candidates with a degree in immunology, cancer biology, haematology, or a related biomedical discipline, and a strong interest in translational immunotherapy. Experience in mammalian cell culture, flow cytometry, molecular cloning, viral vectors or immune functional assays would be advantageous, but comprehensive training will be provided.

Potential placements

1. Sara Ghorashian, Great Ormond Street Institute of Child Health, UCL
2. Dominique Bonnet, Francis Crick Institute
3. Saeed Shoaie, Centre for Host-Microbiome Interactions, King’s College London

References

1. Karantanos T, DeZern AE. Biology and clinical management of hypoplastic MDS: MDS as a bone marrow failure syndrome. Best Pract Res Clin Haematol. 2021;34(2):101280. doi: 10.1016/j.beha.2021.101280.
2. Kadia TM, Huang M, Pemmaraju N, et al. Phase 1 Study of CK0801 in Treatment of Bone Marrow Failure Syndromes. NEJM Evid. 2024;3(6):EVIDoa2300362. doi: 10.1056/EVIDoa2300362.
3. Lim SP, Costantini B, Mian SA, et al. Treg sensitivity to FasL and relative IL-2 deprivation drive idiopathic aplastic anemia immune dysfunction. Blood. 2020;136(7):885-897. doi: 10.1182/blood.2019001347.
4. Huang M, Ke Z, Lyu MA, et al. CXCR4-enriched T regulatory cells preferentially home to bone marrow and resolve inflammation. iScience. 2024;27(9):110830. doi: 10.1016/j.isci.2024.110830.
5. Geissler K, Kabrna E, Kollars M, et al. Interleukin-10 inhibits in vitro hematopoietic suppression and production of interferon-gamma and tumor necrosis factor-alpha by peripheral blood mononuclear cells from patients with aplastic anemia. Hematol J. 2002;3:206-213. doi: 10.1038/sj.thj.6200174.