Yenan Bryceson

Inborn errors of immunity (IEI) cause susceptibility to severe infections,  autoimmunity and cancer, leading to poor survival. An early molecular diagnosis is key to developing precision medicine and guiding personalized treatments, determining the need for curative allogeneic hematopoietic stem cell transplantation (HSCT). HSCT carries risk of mortality but, when warranted, delays increase the risk of fatal complications. In Sweden, more than 220 patients undergo genome sequencing for suspected IEI each year. Only 29% obtain a molecular diagnosis. Current bioinformatical analyses largely ignore vast non-coding genome sequences. Based on expertise in bioinformatics and gene regulation, we have developed a unique functional genomic pipeline optimized to uncover pathogenic non-coding IEI variants. Within a national program, we aim to use this innovative pipeline to increase the diagnostic yield of pediatric patients with suspected IEI. Children with early onset severe disease yet lacking a molecular diagnosis by established clinical genome sequencing are eligible. In a prospective Phase I trial, we will target 60 patients that lack a molecular diagnosis after standard clinical genome analyses. We aim to achieve a molecular diagnosis in at least 20% of unexplained paitents. Importantly, our proof-of-principle methodology can be adapted for improved diagnostics of other forms of genetic diseases, increasing the efficacy of genetic investigations.

Cancer is the second most common cause of death in Sweden. Recent breakthroughs in cancer therapy, e.g. check-point blockade and chimeric antigen receptor (CAR) T cells, highlight the potency of the immune system in controlling and eradicating cancer, but also its limitations in combating many forms of solid tumors. Major efforts are needed to better target cancer and enhance the homing, persistence and function of effector immune cells, requiring close collaboration between basic and clinical scientists. Our goal is to create a vibrant multidisciplinary center that bridges expert knowledge in the biology of cytotoxic lymphocytes – immune cells that kill cancer cells – with that of good manufacturing practice compliant production and adoptive cell therapy in the clinic. Thereby, we will foster innovative new adoptive cell therapies focused on tumor-directed lymphocytes. A major emphasis will be on recruiting and supporting outstanding young principal investigators as well as postdoctoral researchers dedicated to engineering of lymphocytes for cellular therapy of cancer. We will also establish a program for internationally leading visiting scholars to invigorate discussions and innovation within our unique research constellation. Scholars will also contribute to teaching of workshops and graduate courses. Altogether, our efforts aim to expand competence and create an international leading platform within a rapidly developing field of living drugs against cancer.

Certain types of white blood cells, an important component of the immune system, can recognize and kill tumor cells. These cells are called killer cells. Inherited defects that affect the function of killer cells, especially their cell-killing function, can lead to various types of serious diseases such as blood cancer. Studies of patients have increased knowledge of how so-called killer cells are formed and kill target cells. These insights have also led to more targeted and improved treatment of patients with congenital immunodeficiencies. With today's knowledge, however, not all families with suspected immune deficiencies receive a molecular diagnosis. We want to increase understanding of how defects in the immune system can cause an increased tendency to suffer from cancer. We are trying to increase knowledge about the molecular mechanisms that regulate killer cells' ability to recognize and kill target cells. Our research aims to develop sensitive diagnostic methods to detect patients with congenital immunodeficiencies. Targeted killer cells can cure some types of blood cancer, but not most solid tumors. We therefore also want to use our knowledge to improve new, living medicines against various solid tumors, where we want to control the development of killer cells against tumor cells in various tissues. The current research intends to provide increased knowledge about the structure and function of the immune system, especially related to the recognition of tumor cells. It may help us identify new groups of rare patients with severe immune system deficiencies that lead to cancer. By better being able to identify such patients, we can obtain new knowledge about the molecular cause of diseases and better predict which treatment methods may be relevant, which in the long run can reduce suffering and save lives. At the same time, we want to find new ways to target killer cells as a treatment for a larger group of patients with solid tumors.

Pediatric hyperinflammatory syndromes represent a heterogenous group of life-threatening disorders associated with impaired immunity and excessive inflammation. A majority of patients lack a molecular diagnosis and treatments of these conditions are not standardized. There is a critical need for personalized medicine. Building on advanced clinical pipelines and unique patient samples, the specific aims of our proposal are to (1) establish systematic, longitudinal sampling and analyses of pediatric patients with suspected primary immunodeficiency disease (PID), (2) establish systems to evaluate protein-coding variants of unknown significance in genes associated with the most severe PID, (3) identify new PIDs through cutting-edge functional genomic analyses, and (4) determine and understand the pathophysiological mechanisms of novel hyperinflammatory disorders with poor clinical outcome. Our innovative approach combines unique patient material with advanced bioinformatic algorithms and cellular methodology. This proposal is supported by the pioneering translational immunological expertise of the lead investigator and will benefit from a worldwide network of collaborators. Ultimately, we will identify novel molecular causes of hyperinflammatory syndromes which can facilitate personalized medicine. It will also provide proof-of-concept methodology that can be employed in the diagnostics of other unexplained patients with suspected monogenic disease.