Working Party Session
Raffaello (Spadolini -1)
Tuesday, April 1, 09:00 – 10:15
CTIWP Cellular Therapy & Immunobiology Working Party Session
CTIWP-2.1 Targeting TGFβ-activated kinase-1 activation in microglia reduces CAR T immune effector cell-associated neurotoxicity syndrome
Oral Presenter: Janaki Manoja Vinnakota (Germany)
09:05 – 09:25
CTIWP-2.2 Systematic identification of minor histocompatibility antigens predicts outcomes of allogeneic hematopoietic cell transplantation
Oral Presenter: Nicoletta Cieri (United States of America (the))
09:25 – 09:45
In this insightful interview, Janaki Vinnakota1 and Nicoletta Cieri2 speak on their individual, highly commended abstracts, to be presented at EBMT 2025.
Janaki Vinnakota1, Postdoctoral Scholar/Junior Group Leader, University of Freiburg, Breisgau, Germany.
Nicoletta Cieri2, Instructor in Medicine, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
Congratulations on receiving the Jon van Rood Award! What does this recognition mean to you, and how does it reflect the impact of your research?
Cieri: Thank you! Receiving the Jon van Rood Award is a great honour, especially given his foundational contributions to the field of histocompatibility and transplantation. Our work builds on decades of research by many brilliant scientists who have shaped our understanding of alloreactivity and minor histocompatibility antigens. This recognition is not just a reflection of our study but also of the broader effort to bring immunogenetics closer to clinical application. It reinforces the importance of refining our tools to better predict transplant outcomes and, ultimately, improve patient care.
Vinnakota: This award is truly an incredible honour, and I'm deeply grateful for this recognition. This award is not just a reflection of my work but also a testament to the dedication of my mentor, Robert Zeiser, University of Freiburg, Germany, and all our incredible authors and collaborators who played a prominent role in our work. It highlights the impact of our research on a global platform to better understand these immune responses leading to ICANS (Neurotoxicity associated with CAR T cell therapy) and ultimately improve immunotherapies. Knowing that our research is contributing to such advancements that may ultimately improve patient outcomes is incredibly rewarding, and this recognition motivates me to continue further and explore new frontiers in this field.
Can you tell us about your background and what inspired you to pursue this particular area of research?
Cieri: Ever since I was a medical student, I have been drawn to allogeneic transplantation and cellular therapies for haematologic malignancies, as they represent a perfect synthesis of immunology and oncology, two areas that have always intrigued me. After completing my PhD at San Raffaele University in Milan, Italy, and a haematology residency at the University of Milan, I moved to Boston, USA, for a postdoctoral fellowship in Cathy Wu’s lab at Dana-Farber. There, I had the opportunity to learn cutting-edge genomic techniques, which I applied to the allo-HCT field.
Vinnakota: I'm a junior group leader at the University of Freiburg in Germany with Robert Zeiser, and I am trying to establish my independent research group and I am currently a visiting post-doctoral scholar at Stanford, USA. I have a bachelor's and master's in engineering with a focus on biotechnology, which has allowed me to have profound knowledge of basic biology, and it has also helped me to use these concepts to study projects on clinical biology with translational relevance.
Luckily for my PhD, I was recruited on a project that aims to understand the mechanisms of previously unexplored and challenging neurological complications that patients experience after allogeneic stem cell transplantation. To give a small overview, the cancer immunotherapies have dramatically improved patient care, but there are some unintended side effects, which can also affect the central nervous system, resulting in neurological toxicities. These neurological toxicities or complications are incredibly intriguing and are of particular interest because they're quite diverse, and the complications range from mild cognitive impairments, meaning memory loss and confusion, to serious and sometimes life-threatening complications like encephalopathies, neuropathies, seizures, etc. Understanding these mechanisms is crucial for mediating early detection, and developing effective management strategies ensuring improved patient outcomes without compromising the therapeutic benefits of immunotherapies. That’s when I was introduced to this intriguing world of the CNS and microglia. We began exploring the mechanisms of GVHD after allogeneic stem cell transplantation, iRAEs after Immune check point therapies (anti-PD1), and most importantly, ICANS after CAR T cell therapy. We tried to mimic these neurological complications in a mouse setting, and then we compared our findings with the patient samples. And this was inspiring. Altogether, I would say this field is an exciting challenge because it is a pure blend of immunology, neurology, and oncology, with an ultimate goal of maximising the therapeutic potential of these successful cancer immunotherapies while protecting the neurological well-being.
Janaki, please may you summarise your abstract titled ‘Targeting TGFβ-activated kinase-1 activation in microglia reduces CAR-T immune effector cell-associated neurotoxicity syndrome’. What were the key findings, and what are the next steps for this research?
Vinnakota: We have developed two syngeneic ICANS mouse models (B-ALL and B-NHL) to better understand the pathomechanisms associated with ICANS. We observed increased expression of VCAM-1, indicating endothelial activation and alongside increased blood brain barrier permeability upon CAR T cell transfer. We identified microglia were activated and released pro-inflammatory markers such as TNF, GMCSF and MCP-1 upon CAR T cell transfer. In addition, we observed that CAR T cell transfer was associated with cognitive decline and increased anxiety in mice. The cognitive deficits were, however, rescued upon pharmacological depletion of microglia by CSF-1R inhibitor and genetic approach, indicating a prominent role for microglia in mediating ICANS. Additionally, we observed activation of TGF-beta activated kinase (TAK1) signalling in our ICANS mouse models. Pharmacological inhibition of TAK1 with a small molecule inhibitor Takinib, reduced microglial activation, rescued cognitive deficits, and synergistically improved the anti-tumour efficacy of CAR T cells, thereby providing a rationale for testing Takinib in clinical trials. We finally corroborated our findings in ICANS patient samples by performing imaging mass cytometry and identified increased myeloid activation in the CNS. Additionally, we employed TSPO-PET imaging as a diagnostic tool to detect myeloid and microglial changes in patients receiving CAR-T cells. As a next step, we will explore innovative strategies to mitigate ICANS to improve the safety of these immunotherapies.
Nicoletta, please could you summarise your abstract, titled ‘Systematic identification of minor histocompatibility antigens predicts outcomes of allogeneic hematopoietic cell transplantation’. What were the key findings, and what are the next steps for this research?
Cieri: Our study established a framework for systematically identifying minor histocompatibility antigens (mHAg) starting from whole-exome sequencing of donor-recipient pairs and integrating both transcriptomic data and immunopeptidomics. We showed that patient-specific mHAg repertoires could predict the risk of acute and chronic graft-versus-host disease (GvHD) and identify promising graft-versus-leukaemia targets in transplants from matched-related donors. Moving forward, we aim to validate and extend these findings across different donor types – including matched unrelated, mismatched unrelated, and haploidentical donors, as well as newer transplant platforms, such as post-transplant cyclophosphamide (PTCy)-based regimens in larger and more ethnically diverse patient cohorts.
How do you see your findings influencing clinical research or patient care in the future? What are your next steps following this research?
Cieri: The field of medicine is increasingly embracing personalised approaches, and in allo-HCT, this could involve incorporating the assessment of the patient-specific alloreactive potential. This includes mHAgs alongside other immunogenetic factors, such as major HLA mismatches studied by other groups (such as HLA-DP permissivity/expression and B-leader sequence matching). Looking ahead, we envision risk prognostication models that integrate immunogenetic and clinical variables, potentially enhanced by AI, to optimise donor selection and tailor GvHD prophylaxis.
Vinnakota: Our findings have significant potential to influence clinical research and patient care, particularly in the management of CAR-T cell therapy-related toxicities like ICANS. We have demonstrated that myeloid cells, especially microglia in the central nervous system, are activated through TNF, GM-CSF, and TAK1 signalling pathways. This provides a strong rationale for testing either CSF-1R inhibitors to deplete microglia or TAK1 inhibitors as targeted treatment strategies in clinical trials for patients. Furthermore, building on these findings, there are ongoing clinical trials exploring the use of non-invasive TSPO-PET imaging to detect myeloid activation in patients receiving CAR-T cells. This could lead to earlier detection, better monitoring, and more effective interventions, ultimately improving patient outcomes.
The next steps involve exploring the pathomechanisms of immune-related neurological adverse events that arise after anti-PD-1 therapy, where we have identified a prominent role for SYK signalling. We found that SYK kinase inhibition can reverse these immune-related neurological adverse events in our mouse models. We are now studying whether our findings can be applied in clinical trials for treating these complex neurological complications that arise after cancer immunotherapies.
As cancer immunotherapy continues to evolve, the incidence of neurotoxicity is alarmingly increasing. I wish to continue exploring the neurological complications associated with emerging immunotherapies and understand their pathomechanisms aiming to identify new therapeutic targets and enhance the safety of these successful immunotherapies.
Your research involves innovative methodologies to address key challenges in the field. What were some of the biggest obstacles you faced during the study, and how did you overcome them?
Cieri: Alloreactivity and immunogenetics have traditionally relied on forward immunology approaches, which have been instrumental in defining the fundamental rules of T cell allorecognition. However, to make these insights applicable at scale across diverse patient populations and HLA backgrounds, we must also embrace predictive and reverse immunology approaches. These methods come with challenges, including false positives and the difficulty of experimentally validating large-scale predictions. Scepticism often arises from the inability to functionally confirm every predicted antigen. To address this, we integrated multiple layers of evidence, genetic, transcriptional, and immunopeptidomic, to enhance the biological relevance of our findings. I find a useful parallel in the tumour mutation burden metric for checkpoint blockade in solid tumours: not every mutation generates an immunogenic neoantigen, yet mutation load remains a powerful tool for identifying patients most likely to benefit from therapy.
Vinnakota: The major hurdles that we faced during this project were mainly mimicking the patient scenario in our preclinical mouse models and unravelling these complex mechanisms, as ICANS are generally influenced by a plethora of factors, including patients' immune status, tumour burden, and their treatment regimens, etc. We had to carefully adjust several factors in our models so that we could recapitulate these scenarios, starting from doses of CAR-T cells, checking the cytokine profiles, endothelial damage, and also disease progression timelines to align with what we see in the patients. This required extensive mouse model optimization and complex experimental designs. Another challenge was correlating our preclinical findings with patient data. The acquisition, availability and analysis of ICANS patient post-mortem brain tissues was difficult, we are grateful to our collaborators from Neuropathology department, Freiburg, University medical centres in Germany and USA who played a crucial role in helping us overcome these obstacles.
What is the presentation or event you liked the best at this Annual Meeting?
Cieri: The programme is very exciting, with many sessions I’m planning to attend. EBMT holds a special place in my career. It was the first conference I ever attended as an undergraduate student, and I participated regularly while I was at San Raffaele. It has always been a great forum for exchanging ideas, staying at the forefront of transplant research, and fostering meaningful collaborations within the field.
Vinnakota: All the sessions look very interesting and I am planning to attend the sessions on GVHD, CAR T-cell therapy, toxicities, as well as those on bispecific and multiple myeloma, among others. I’m excited to gain deeper insights into the latest advancements and challenges in these areas at the EBMT.
Editorial Team: 