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EBMT 2021 Annual Meeting - Jon van Rood Award

by
Cellular Therapy & Immunobiology Working Party (CTIWP)

EBMT 2021 Jon van Rood Award: Franziska Uhl

AA2 Abstracts Awards

Tuesday, March 16, 17:30 - 18:00, Auditorium 1

This year’s Jon van Rood Award has been given to Franziska Uhl for her study “Metabolic reprogramming of donor T cells enhances graft-versus-leukaemia effects in mice and humans”.

You can read the full abstract and paper, published in Science Translational Medicine, here: https://www.abstractserver.com/JonJvanRood.pdf

Here, we find out about Franziska and her career.

Q: Congratulations on your award Franziska. For our delegates that do not know you, can you tell us a little about yourself and where you are based?

A: Thank you very much, it is a great honour for me to receive this award!

I am a biologist by training with a special focus on immunobiology. During the course of my studies and several internships I developed a deep interest in the interface between immunology and cancer research. My passion is the transfer of scientific discoveries into clinical applications. The last years, I have been working on my PhD thesis in the lab of Prof. Robert Zeiser at the University Hospital Freiburg in Germany.

Q: Tell us about the focus of your research and your day-to-day work?

A: The research we published focuses on tumour immunology in the setting of leukaemia. We were interested in the dynamic metabolic changes shaping the immune function of T cells, the main players orchestrating the graft-versus-leukemia effect after allogeneic hematopoietic cell transplantation (allo-HCT). The lab is located at the University Hospital Freiburg and we have built successful collaborations with labs of the University Freiburg and the Max-Planck-Institute both renowned for their strong immunology research. Therefore, we were able to combine our translational research using patient samples and in vivo GvL models with extensive in vitro studies and high-throughput approaches.

Q: Why did you decide to do this study?

A: Despite major developments in recent years, treatment options and outcome of patients relapsing with AML after allo-HCT are still poor. We wanted to better understand how leukaemic cells escape the immune system and if metabolic changes play a role which could be antagonized by nutrient supplementation or medication. The metabolic dynamics influence every aspect of a T cell’s life including development, survival and function. We hypothesized that the selection pressure after allo-HCT favoured leukaemic cells which interfered with the metabolic dynamics of T cells and impaired effective immune responses. We wanted to develop a treatment strategy aimed at boosting T cell metabolism to improve outcome after relapse.

Q: You have a large number of collaborators, tell us about some of the other centres that were involved in the work?

A: I am very grateful to all our collaboration partners who supported this study with great experimental support and thoughtful advice. I would like to highlight the wonderful and very productive collaboration with the group of Erika Pearce, formerly located at the Max-Planck-Institute in Freiburg and now transferred to Baltimore. Their extensive expertise regarding T cell metabolism guided us through some tough questions we were facing. Their support of the metabolomic analyses was essential for the study. Other collaborators I would like to mention include the group of Melanie Börries, also located in Freiburg, helping with the transcriptomic analysis and the group of Tobias Madl in Graz, Austria, who performed the NMR analysis of cell culture supernatants. In particular, I would like to emphasize the fantastic teamwork within the University Hospital Freiburg. The analysis of the patient samples was a joint effort of clinical staff coordinating patient treatment and sample collection as well as us in the lab performing the extensive analyses. Thanks again to everyone, who has contributed to this study!

Q:  What were the main findings of the study, and how can they be applied in practice?

A: We discovered a major defect in T cell metabolism in patients with an AML relapse after HCT which was reflected in an impaired immune phenotype. We could identify lactic acid as the metabolite secreted in large amounts by the AML blasts at the time point of relapse. Lactic acid mediated the downregulation of key metabolic pathways and interfered with the proliferative capacity of the T cells. This led to an inadequate immune-mediated leukaemia control. The effect was mediated by reduction of the intracellular pH as well as fundamental changes in T cell metabolite composition. We developed a treatment strategy using sodium bicarbonate (NaBi) that increased the intracellular pH, restored the metabolic and signalling pathways and even allowed for lactic acid metabolisation as an additional energy source in T cells. We could prove the beneficial effect of NaBi in several murine GvL models. After working from bedside to bench, we went back to bedside and treated a small cohort of patients with AML relapse under donor lymphocyte infusion therapy with NaBi. Bicarbonate delivered a metabolic boost rendering the T cells with an improved metabolic and immune phenotype.

Therefore, we propose larger clinical trials to investigate the long-term benefit for the patients. In our small study, the metabolic phenotype of T cells was independent of the mutational landscape of the AML so we are optimistic that the administration of NaBi could benefit many patients. We also expect benefits for combination treatments using a metabolic modulator such as bicarbonate together with other immunotherapies including checkpoint blockade.

Q: What other projects are you involved in at the moment?

A: I am currently finishing my doctoral thesis, so my main focus right now is studying and getting ready for the defense in a few days. Besides, I have been involved in a few other projects which are just before completion. One project investigates mechanisms of graft-versus-host disease in the GI tract. Additionally, I have been supporting a collaboration partner analyzing the impact of febrile temperatures on T cell metabolism. Since this year, I am taking my first steps into industry because I want to support the development of new therapies through clinical studies into the clinical practice and I want to contribute my knowledge and passion regarding haematology and immunology to help get new treatments to patients.

Q: Who would you like to mention in relation to receiving this award?

A: First of all, I would like to give a big thank you to my mentor Prof. Robert Zeiser who gave me the possibility to work on this fantastic project and who supported and motivated me throughout these years. I want to thank my wonderful lab colleagues who became great friends over the years. Together, we withstood even the challenging times with fun and good humour. My biggest thanks go to my friends, my boyfriend and my family for the unconditional support and the belief that I should always follow my interests and dreams. At last, I want to thank the EBMT for conferring the award to our study underscoring the importance of our work. This further strengthens my motivation to help improving the life of cancer patients.