Abstracts Award Ceremony - Monday 31 August, 18:05 – 18:35H, Auditorium 1
Jon J. van Rood Award 2020: Cristina Toffalori
This year’s Jon van Rood Award has been given to Dr Cristina Toffalori for her study “Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation”.
Here, we find out about Cristina and her career, as well as her joy at becoming a mother.
Q: Congratulations on your award Cristina. For our delegates that do not know you, can you tell us a little about yourself and where you are based?
A: I am Cristina Toffalori, I am 36 years old and I grew up in Milan. In the last couple of years my life remarkably changed, since I have become the mother of a beautiful baby boy! Ever since, I had to better organise and plan my daily life in the lab to be able to manage family and scientific activities.
I am a senior post-doc in the “Unit of Immunogenetics, Leukemia Genomics and Immunobiology” headed by Luca Vago at the San Raffaele Scientific Institute of Milan.
Q: Tell us about the focus of your research and your day-to-day work?
A: My research focuses on the immunobiology of leukaemia in the setting of allogeneic haematopoietic stem cell transplantation, and in particular on the mechanisms of leukaemia immune escape and relapse. During the last years, also thanks to a “Young Research Grant” award, I am widening my research area trying to uncover the complexity of the entire bone marrow immune microenvironment in the context of relapse after allogeneic transplantation.
All my projects require a daily interaction not only with the scientific community but also with the clinics and physicians. The San Raffaele Scientific Institute offers a solid base for translational research, synergising the activity of a hospital, a research institute and a university, and it is considered one of the leading research institutes in Italy.
The role of the immune system in cancer could be considered a double-edged sword. This is a paradigm that has always fascinated me. While there is evidence that a strong immune system can be beneficial, in many cases the immune system clearly promotes tumour growth. To study these reciprocal interactions, haematological malignancies and allogeneic transplantation represent a unique and peculiar setting. I had the chance to get involved in such work during my PhD when I got involved in the project that ultimately ended in our Nature Medicine paper, awarded this year with the Jon van Rood Award 2020.
To view the Nature Medicine paper, see: https://www.nature.com/articles/s41591-019-0400-z
Q: Why did you decide to do this study?
A: Transplantation of haematopoietic cells from a healthy individual is one of the most effective treatment for acute myeloid leukaemia, thanks to the anti-tumour capacity of the transplanted immune system, capable to detect and eradicate residual tumour cells through an effect termed graft-versus-leukaemia.
Unfortunately, leukaemia reappearance after transplantation remains frequent, representing a largely unmet medical issue accompanied by significant emotional and social impact.
Our lab provided a relevant first example on how leukaemic cells evade immune recognition, by demonstrating that after transplantation from partially incompatible donors they frequently undergo selective genetic loss of the histocompatibility molecules recognised by the transplanted immune system, becoming in this way virtually undetectable.
The aims of this study were to investigate whether immune escape could also explain other cases of post-transplantation relapse.
Q: You have a large number of collaborators, tell us about some of the other centres that were involved in the work?
A: This study takes advantage of the cooperation of specialists in different fields, mixing clinical, biological and computational know-hows, and of scientists from centres distributed globally, located both inside and outside Europe.
Importantly, most of the collaborators are part of national and international transplantation centres that are well-known not only for their clinical activity, but also for their high-quality research studies. The Italian centers involved in the study were the Bone Marrow Transplantation unit of “Ospedale San Raffaele” headed by Fabio Ciceri and the unit of Professor Alessandro Rambaldi from Bergamo. Among the European centers the Haematology and Transplantation units from Freiburg (coordinated by Jurgen Finke and Robert Zeiser), Essen (headed by Dietrich W. Beelen), Leiden (headed by Marieke Griffioen) and Marseille (coordinated by Didier Blaise) were involved. Moreover, other two non-European haematology centers collaborated: the Johns Hopkins University School of Medicine (headed by Leo Luznik) and the Sapporo University (coordinated by Takanori Teshima).
So, this broad and international network was exploited to be able to rapidly get access to a sufficient number of longitudinally collected and viable leukaemia samples in order to include in the study, besides our internal cohort, also an independent series of patients. In translational research, especially if it leverages human primary samples, the validation of the observations and of the results on independent cohorts broadens the value of the research itself and of the main findings obtained.
Finally, along with our manuscript mentioned above, another paper was released in the Nature Communication journal. In this work the group of Professor Chiara Bonini, with whom we have a long-lasting active collaboration, described, in line with our results, that in post-transplantation follow-up time points, the T cell compartment resident in the bone marrow also acquires a dysfunctional phenotype with impaired activity that is more pronounced in patients experiencing a relapse compared to non-relapsing patients.
To view the Nature Communications paper, see: https://www.nature.com/articles/s41467-019-08871-1
Q: What were the main findings of the study, and how can they be applied in practice?
By taking advantage of high-throughput next generation sequencing and immunofluorescent technologies, we analysed leukaemic cells and immune lymphocytes longitudinally collected during patients’ disease and treatment history from two independent cohorts transplanted in ours and other international institutes. Through this analysis we revealed two novel non-genomic, epigenetic mechanisms exploited by tumour cells to survive: on the one hand, leukaemia cells reduce the expression of HLA molecules on the surface, thus hiding from lymphocyte surveillance; on the other hand, they increase the presence of specific immunosuppressive receptors that tell lymphocytes to slow down their activity, turning off the immune response.
Based on each of the identified immune evasion mechanisms, specific therapeutic interventions could be implemented, including induction of a controlled inflammatory state that would then raise the blood levels of interferon, a molecule that promotes the expression of HLA molecules. On the contrary, if the relapse is explained by the tumour turning off the activity of T lymphocytes, patients could be treated with immune checkpoint inhibitors, drugs that re-activate T lymphocytes and turn on the immune response. In both cases, making the wrong treatment choice could not only be ineffective, but even harmful.
Understanding the biology of leukaemia relapse after transplantation is a key point to make a step forward to the treatment of post-transplantation leukaemia relapses. Being able to stratify the patients according to leukaemia-relapse specific features means to be able to design new therapeutic strategies, maximising treatment efficacy and reducing toxicity.
Q: What other projects are you involved in at the moment?
A: All the modalities at the base of leukaemia post-transplantation relapse appear to be primarily prompted by the selective pressure mediated by alloreactive and leukaemia-specific donor T cells. However, it is still largely unknown and poorly characterised how the rest of the bone marrow collaborates or adapts to these events, and why it fails to enact measures to counteract them.
Hence, by taking advantage of cutting-edge single cell technologies comprising single cell RNA sequencing and multiplex immunofluorescence of bone marrow sections, my present work aims at clarifying how the bone marrow immune microenvironment changes in each of these relapse modalities. Understanding and exploiting the full complexity of the bone marrow microenvironment would better fulfil the idea of "normalising" the immune system. We believe that therapeutic strategies leveraging on multiple cell subsets that operate in synergy and recognise different targets, could significantly reduce the risk of selecting leukaemia escape variants, thus reducing the rate of disease relapse after transplantation.
Q: Who would you like to mention for receiving this award?
A: Firstly, I would really like to thank the CTIWP Award Committee for selecting our work for the prestigious Jon J van Rood Award 2020. It is important for us to receive such an acknowledgement of the relevance of our work for the EBMT scientific community, strengthening my commitment in pursuing my career path on these topics.
At the end of a project, due thanks are necessary for the help of all the collaborators and all the people that made this possible. In particular, I would here like to thank Dr. Luca Vago, my mentor since my PhD internship, for his daily support toward my scientific maturation and independence.