Cancer Immunology

Cancer Immunology Group

Group Leader: Prof. Natalia Marek- Trzonkowska, PhD

Professor of Medical Sciences, speciality immunology

Main research focus: immune tolerance, cellular therapies, cancer, autoimmunity, Tregs, intercellular interactions

e-mail: natalia.marek-trzonkowska@ug.edu.pl

telephone: +48 58 523 34 64

 

Academic career

In 2005 she was graduated with honors at Faculty of Veterinary Medicine at University of Warmia and Mazury (UWM) in Olsztyn and received the title of veterinary medicine doctor. She was awarded with three independent prizes for the best student of the faculty in years 1999-2005 by Chamber of Veterinary Medicine Doctors of Warmia and Mazury, Dean of the Faculty of Veterinary Medicine of UWM and Polish Small Animal Veterinary Association and Iams Procter & Gamble Company. In 2010 she defended her PhD doctoral dissertation „Selected mechanisms of activation of the immune system in type 1 diabetes” at Faculty of Medicine of Medical University of Gdańsk (MUG, Gdańsk, Poland) and was awarded a PhD degree in medical sciences with cum laude. In 2010-2011 she has been working as a postdoctoral fellow at the Department of Surgery at University of Chicago (Chicago, USA) as awardee of Kosciuszko Foundation. She was a member of Islet Transplant Group focused on isolation of human pancreatic islets for clinical and research purposes. During this time her work was focused on novel approaches for local and systemic immunoprotection of transplanted islets that included exploiting poly (ethylene glycol) for islet coating with living regulatory T cells (Tregs) and treatment with ex vivo expanded autologous Tregs, respectively. In 2013 she defended her habilitation thesis „Regulatory T cells as a therapeutic tool in type 1 diabetes” at Faculty of Medicine of Medical University of Gdańsk. In 2016 she completed an internship at National University of Ireland in Galway (Ireland) thanks to stipend funded by Action to Focus and Accelerate Cell-based Tolerance- inducing Therapies (A FACTT) of European Cooperation in Science and Technology (COST). In 2019 she was awarded the professor degree in medical sciences by President of the Republic of Poland. In 2018 she joined International Centre for Cancer Vaccine Sciences (ICCVS) as a leader of Cancer Immunology group. In 2021 she became an acting director of the Centre and leader of ICCVS project, while in 2022 she was approved by International Scientific Committee of ICCVS, Foundation for Polish Science (FNP) and rector of University of Gdańsk the director of ICCVS and leader of the ICCVS project.

Research

Regulatory T cells- biology and clinical application

Prof. Natalia Marek- Trzonkowska is a co-PI of the first in man clinical therapy of GVHD and type 1 diabetes (T1D) with regulatory T cells (Tregs; doi: 10.1016/j.clim.2009.06.001, doi: 10.2337/dc12-0038). In June 2008 her team administered for the first time expanded in vitro Tregs to the bone marrow recipient with chronic graft versus host disease (GVHD). After Treg injection a significant clinical improvement was observed, thus the immunosuppressive therapy could be tapered increasing quality of the patient’s life. This was the first clinical application of Tregs in human. Its results were published in 2009 in Clinical Immunology journal („First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells” Clinical Immunology, doi: 10.1016/j.clim.2009.06.001). The further clinical trial recruited 20 GHVD patients and confirmed safety of Treg administration in human, paving the way for further clinical studies with Tregs.

In the next years she was also a co-leader of the first Treg therapy in T1D. In March 2011 her team administered ex vivo expanded autologous Tregs to diabetic pediatric patient. The aim of the therapy was to stop ongoing destruction of pancreatic b cells. The clinical trial showed that Treg treated patients are characterized by increased insulin secretion and decreased levels of anti-islet antibodies as compared with not treated children that suggests protective effect of the therapy on b cells.  Individuals who received Treg infusion stayed longer in remission, as they were characterized by higher C-peptide levels and minimal requirement for exogenous insulin (daily dose of insulin; DDI ≤0.50 UI/kg; Marek Trzonkowska et al. 2011 Diabetes Care, doi: 10.2337/dc12-0038; Marek Trzonkowska N et al 2014 Clin Immunol, DOI: 10.1016/j.clim.2014.03.016; Marek- Trzonkowska N et al J Transl Med 2016, doi: 10.1186/s12967-016-1090-7). At the same time untreated children receive two-fold higher insulin doses and show a significant decrease in b cell activity over time. Furthermore, a year after diagnosis of DM1 among 12 treated children, 2 were still independent on exogenous insulin. Subsequently, the next 12 patients were treated. In 2023 the results of the third trial called TregVAC2.0 (no. EudraCT:2014-004319-35) were published in which diabetic children received Tregs alone or in combination with anti-CD20 antibody.

During the years, the protocol of the therapy was substantially improved due to prof. Marek- Trzonkowska studies on Treg biology (US patent US 11,072,779 B2, Polish patent 236046, patent applications submitted to EPO EP20202379.2, EP20202376.8). Currently, the longest period of insulin independence that can be achieved after the therapy is equal to 18 months. However, the main benefit from the treatment is lack of diabetic complications, well controlled glycemia and lack of life-threatening hypoglycemia episodes in treated individuals.

During her postdoctoral fellowship at University of Chicago (USA) she was a member of the Islet Transplant Group at the Department of Surgery where she has been working on isolation of human pancreatic islets at GMP (Good Manufacturing Practice) facility for clinical and research purposes. She also elaborated a method of local protection of transplanted islets from immune response of the recipient. The method was based on islet coating with living Tregs that worked as both- physical barrier and active defense against immune response of the recipient.

Intercellular interactions

Cell therapies can become a safe and effective method of treating many human diseases, including cancer, autoimmune diseases or excessive inflammatory reactions that take place in sepsis or during viral infections (including COVID-19). However, to achieve this goal, it is essential to know the mechanisms of intercellular communication in order to predict the behaviour of cells when administered to a patient.

All immune responses are initiated with direct cell-to-cell contacts, as well as indirect interactions where cells in different locations influence themselves via secreted mediators and extracellular vesicles (EVs). The knowledge how to affect these interactions creates great opportunities for regulation of the immune reactions. Thus, stimulating or suppressing contacts of certain cellular populations a researcher can reach a desired therapeutic effect for treatment of autoimmunity and cancer.

Studies conducted by prof. Marek- Trzonkowska showed that plasma membrane potential of CD4+ T cells is a subset specific feature and at the same time is modulated in specific manner by direct contact with other cells. Membrane potential of T cells is affected by direct cell-to-cell interactions and its values result from quantity and quality of these direct contacts.  This knowledge can be used for elaboration of strategies for specific cell function modulation in various human and animal diseases.

During her studies she also characterized unknown mechanisms of intercellular communication between mesenchymal stem cells (MSCs) and Tregs. She demonstrated that MSCs transfer mitochondria to allogeneic Tregs in an HLA-dependent manner improving their immunosuppressive activity. This phenomenon was found to improve Tregs’ potential for accumulation of immunosuppressive adenosine and suppression of conventional T cell proliferation, making them more potent therapeutic tools. In addition, she proved that mitochondria transfer in allogenic model is HLA-dependent and correlates positively with HLA-C and HLA-DRB1 eplet mismatch load between Treg and MSC donors (Nature Communication 2022, doi.org/10.1038/s41467-022-28338-0).

This knowledge is also of clinical importance as sheds new light on tumour- microenvironment interactions and mechanisms of tolerance induction in allograft transplantation. In addition, Treg- MSC coculture leads to generation of more potent Tregs for clinical applications (2 patent applications submitted to EPO EP20202379.2, EP20202376.8)

 Immunology of pregnancy- the perfect model of immune tolerance to foreign antigens

Pregnancy is a unique physiological state that can teach us a lot about immune tolerance mechanisms. This knowledge is useful for treatment of both autoimmunity and cancer that are in fact the two sides of the same coin (Frontiers in Immunology 2022, doi: 10.3389/fimmu.2022.793234). The foetus shares half of the genome with mother and half with the father, thus it is semi-allogeneic to the maternal immune system. In this term pregnancy resembles allograft transplantation. Therefore, induction of fetal tolerance is crucial for its survival, development, and full-term pregnancy. However, unlike the allograft recipients, pregnant women does not need any treatment to induce and keep foetal tolerance in physiologic pregnancies. Studies of prof. Marek- Trzonkowska are focused on NK and T cell recognition of foetal antigens and their switching into tolerant mode. In her studies she analyses impact of killer immunoglobulin-like receptors (KIR) as well as HLA class I and class II eplets on these responses (Frontiers in Immunology 2022, doi.org/10.3389/fimmu.2022.868175). She is convinced that studying immune mechanisms from various, usually opposite, angles will result in deep understanding of cancer evasion from immune system surveillance, as well as will provide hints how to restore immune tolerance in autoimmunity.

Personalized T cell-based therapies of non-small cell lung cancer (NSCLC)

 Prof. Marek- Trzonkowska has developed the algorithm for identification and isolation of cancer-specific T cells. Sorted cells (FACS) are then expanded, stimulated, and characterized in vitro. Simultaneously, her team establishes primary cancer cell lines and cultures of the cells derived from healthy lung tissue of the same patient which are crucial for efficacy and safety testing. The current data show that selected lymphocytes efficiently kill the patient’s cancer without attacking normal cells. This significantly reduces the risk of adverse effects. For each patient, a different lymphocyte population is sorted. This personalized approach takes into account the individual characteristics of each tumour and patient immune system.

Simultaneously, her team has been working on another strategy, where identification of neoantigens precedes T cell selection. ICCVS team has elaborated a method for removal of peptides presented by MHC class I molecules of various tissues (including NSCLC). In further steps the peptides are identified and quantified with mass spectrometry and bioinformatic approaches. In addition, the team elaborated a pipeline for identification of tumour unique peptides (neoantigens) among all collected peptides. With this knowledge neoantigen specific lymphocytes can be isolated from the patient’s blood. Prof. Marek- Trzonkowska is convinced that both methods developed by her team for obtaining therapeutic cells will work complementarily. Currently, the experiments in vivo with patient derived xenograft (PDX) mice model are ongoing. The clinical trial is planned in close perspective.

In parallel the studies on tumour microenvironment including tumour- host communication via extracellular vesicels (EVs) are ongoing. The team has been also working on development of new adjuvants for T and NK cell stimulation ex vivo and deciphers impact of hypoxia on T cell cytotoxicity.

Research projects

  • 2022-2025 “Enhancing Cancer Vaccine Science for New Therapy Pathways (CANVAS)”, Twinning project, Horizon Europe, project no. 101079510, coordinator of the project
  • Since 2018 „International Centre for Cancer Vaccine Science (ICCVS)”, project carried out within the International Research Agendas programme of the Foundation for Polish Science (FNP) and the European Union under the European Regional Development Fund, project no. MAB/2017/3 (budget 12 000 000 Euro); 2018-2020 Leader of Cancer Immunology group, 2020-2021 Acting Director of the Centre and leader of the project, since 2022 director of the Centre and leader of the project
  • 2016-2019– “Analysis of antigen specific regulatory T cells in children with recently diagnosed type 1 diabetes”, National Centre for Research and Development, project no.: LIDER/160/L-6/NCBR/2015
  • 2015-2019– “The importance of mother-fetus HLA eplet incompatibility in the pathogenesis of pregnancy induced hypertension”, National Centre of Science, project no.:UMO-2014/15/B/NZ5/03499, coordinator of the project
  • 2013-2018– “Proangiogenic activity of serum from patients with selected clinical conditions”, National Centre of Science, project no.:UMO-2012/07/B/NZ5/00017, coordinator of the project
  • 2012-2017– “Significance of heat shock proteins for the activation and proliferation of regulatory T cells cultured for the clinical purposes”, Ministry of Science and Higher Education, project no.: 0337/IP1/2011/71, principal investigator and coordinator of the project
  • 2012-2017- “Interactions between regulatory T cells and allogeneic mesenchymal stem cells”, National Centre of Science, project no.:UMO 2011/01/D/NZ3/00262, type of participation in the project- principal investigator and coordinator of the project
  • 2014-2018- “Cellular therapy with ex vivo expanded CD4+CD25+CD127- T regulatory cells”- studies realized within strategic programme of research and development „Prophylaxis and therapy of cavillation diseases”, National Centre for Research and Development, project no.: STRATEGMED1/233368/1/NCBR/2014
  • 2011-2014- “New medical techniques based on immunotherapy”, National Centre for Research and Developmentt, project no.: NR13-0126-10, type of participation in the project
  • 2011- “Feasibility of in vitro expansion of regulatory T cells for adoptive immunotherapy of potential recipients of pancreatic islets”, Kosciuszko Foundation, principal investigator and coordinator of the project
  • 2010-2011- “Pancreatic Islet Transplantation”, Illinois Department of Public Health, USA
  • 2009-2011- “Activation of regulatory lymphocyte subsets after allogeneic transplantations”, Medical University of Gdansk, project no.: ST-49
  • 2008-2011- “Molecular mechanisms associated with expression of soluble (sTNF) and membrane-bound (tmTNF) form of TNF-α and its correlation with development of diabetic retinopathy in type 1 diabetes. Modulation of activity of TNF-α as a potential tool of prophylaxis and therapy of diabetic retinopathy in children”, Ministry of Science and Higher Education, project no: NN 407 173034
  • 2006-2009– “Searching for the early pathogenetic mechanisms of diabetic retinopathy”, Ministry of Science and Higher Education, project no.: N401 085 31/1973, principal investigator and coordinator of the project

The most important scientific awards

Award of the Minister of Education and Science for Outstanding Achievements in Implementation of Scientific Discoveries into Clinical Practice (2023), the Scientist of the Future Award in category Woman Who Changes the World granted by Smart Development Forum foundation (2023), 2 Awards of European Federation of Immunological Societies (EFIS, 2012 and 2015), Stipend of Minister of Science and Higher Education for Outstanding Young Scientists (2013-2016), Award of Polish-American Medical Society (PAMS, 2014), Award of Polish Academy of Sciences (2013), Young Investigator Award granted by the International Society of Pediatric and Adolescent Diabetes (ISPAD, 2012), 2 Awards of the International Islet and Pancreas Transplantation Association (IPITA, 2011), Award of the Main Council of Polish Society of Pediatric Endocrinology and Diabetology (2013), Golden Scalpel- Award for the Outstanding Innovator in Polish Health Protection (2012), Scholarship of Kosciuszko Foundation for realization of the project “Feasibility of in vitro expansion of regulatory T cells for adoptive immunotherapy of potential recipients of pancreatic islets” (2011), Young Investigator Award granted by Polish Diabetes Association (PTD, 2010), Young Investigator Award granted by Scientific Committee of XXVIII Retinologic Symposium in Poland (2007), 1stBasic Science Award granted during 13th International Student’s Scientific Conference in Gdańsk, Poland (2005).

Patents

  1. patent granted by European Patent Office (patent no. 2859092) “ Therapeutic vaccine for treatment of diabetes type 1 in children, application of the cell sorter and the method of multiplying Treg cells to produce therapeutic vaccine for treatment of diabetes type 1”; patent application also submitted to United States Patent and Trademark Office  (application no. 14/405,906)
  2. patent granted by Polish Patent Office (patent 218400) “Szczepionka do leczenia cukrzycy typu 1 u dzieci, zastosowanie sortera komórkowego do wytwarzania szczepionki do leczenia cukrzycy typu 1 oraz sposób namnażania komórek Treg”
  3. patent Granted by United States Patent and Trademark Office (patent no. US 11,072,779 B2) “Method for ex vivo expansion of regulatory T cells”; patent application also submitted to European Patent Office (application no. EP 16834056.0); Continuation-In-Part application (CIP) application submitted (no. 17/381,192)
  4. patent granted by Polish Patent Office (patent no. 236046) “Sposób namnażania komórek T regulatorowych (Tregs)”

Patent applications submitted under evaluation

  1. application submitted to European Patent Office (2020) „ Conditioned regulatory T cell population with enhanced therapeutic potential, method for obtaining of regulatory T cell population and the medical use of regulatory T cell population (application no. EP20202379.2)
  2. application submitted to European Patent Office (2020) „ Conditioned regulatory T cell population Tregs with enhanced therapeutic potential, method for obtaining of conditioned Tregs and the medical use of the Tregs population” (application no. EP20202376.8)
  3. application submitted to European Patent Office (2022) „Novel method for sample preparation for qualitative and quantitative analysis of peptidome in serum based on amino acid sequencing with a tandem mass spectrometry and novel data analysis workflow for quantitative analysis of the peptides sequenced with a tandem mass spectrometry” (application no. 3)
  4. application submitted to European Patent Office (2022) „Serum peptide patterns for diagnostics of intracranial hemorrhagic stroke in humans and differential diagnosis of intracranial hemorrhagic stroke from acute ischemic stroke“ (application no. 1)
  5. application submitted to European Patent Office (2022) „Serum peptide patterns for diagnostics of acute ischemic stroke in humans and differential diagnosis of acute ischemic stroke from intracranial hemorrhagic stroke” (application no. 4)
  6. application submitted to European Patent Office (2023) „Method for high-throughput qualitative and quantitative intracellular peptidomics of mammalian cells” (application no. 5)