Jonas Mattsson's Group
Optimization of allogeneic stem cell transplantation and immunotherapy of cancer
The white blood cells that build up our immune system, the red blood cells that carry oxygen to all body cells, and the platelets that enable the blood to efficiently clot, develop from stem cells located in the bone marrow. Individuals who suffer from diseases that affect the body's blood stem cells such as leukemia, severe anemia, immune defects, and some more unusual enzyme deficiency diseases, need a bone marrow replacement in order to produce new and healthy blood cells. Hematopoietic stem cell transplantation (HSCT), is nowadays an established treatment for these diseases. It consists on the transplantation of multipotent stem cells collected from a donor and is therefore called an allogeneic transplant.
Project 1- Randomized study comparing haploidentical donors with matched unrelated donors in patients with AML
Using HLA-identical sibling donors is generally believed to be the best donor choice and has also been associated to best overall survival. However, only one third of the patients eligible for allogeneic HSCT have HLA-matched siblings. There are today three options for patients lacking an HLA-matched sibling donor: 1) volunteer unrelated donors 2) umbilical cord blood and 3) mismatched related or haploidentical donors. Haploidentical transplantations have during the last years gained increased interest since the success of introducing post-cyclophospamide day +3 and +4 (or +5) which has paved the way for this treatment modality. The possibility to use haploidentical donors is tempting for several reasons; 1) it significantly increases the donor pool and thus offer almost all patients with an indication for HSCT an opportunity to be transplanted, 2) it would provide a possibility to more rapid transplantation since unrelated donor search is not necessary and also increase the chances of immune modulatory measures since the access to a family donor is more rapid and feasible, 3) transplanted cells from related haploidentical donors may also be of better quality compared to using unrelated donors where long transportation time may affect cell quality, 4) it would possibly bring down costs of HSCT. In a recent retrospective analysis in patients with acute myeloid leukemia (AML), patients with matched unrelated donors showed the same outcome as for patients with haploidentical donors. The results for patients with acute leukemia and other hematological malignancies have also been impressive. But prospective, randomized studies are lacking. Therefore we are conducting a randomized multicenter study comparing haploidentical donors with matched unrelated donors in patients with AML.
Project 2- Retrospective analysis evaluating the factors affecting the outcome of patients after HSCT
The clinical information regarding patients who undergo HSCT at the center for allogeneic stem cell transplantation (CAST, Karolinska Hospital Huddinge) collected in a registry is used in order to analyze and identify retrospectively the parameters affecting patients’ outcome.
Project 3- Treatment with CD19 chimeric antigen receptor (CAR) T cells
B-cell malignancies consist of a heterogeneous group of leukemias and lymphomas and despite improvements in treatment strategies many patients, both children and adults, still succumb to the diseases. Leukemia is the most common pediatric malignancy, accounting for 30% of all pediatric cancers. Improvements in the treatments of pediatric acute lymphoblastic leukemia (ALL), including allogeneic HSCT, have achieved cure rates of over 80%, but still relapsed leukemia remains the most common cause of pediatric cancer death. To address the problem of limited success with today’s available treatment for these patients novel cellular therapies using genetically modified, tumor specific T cells have gained interest. It is now possible to efficiently introduce genes encoding CARs into immune effector cells. In most clinical applications, a patient’s own T cells are reprogrammed to express these tumor-specific receptors. To this end, most clinical trials in the field of CAR technology for leukemia have targeted CD19 since it is expressed on most B-cell malignancies.
We are therefore implementing a study in order to assess the feasibility, tolerability and efficacy of administering T-cells expressing an anti-CD19 CAR to children with ALL and with chemotherapy resistant or refractory CD19+ leukemia. This project will increase the chance of cure in patients with otherwise dismal prognosis.
Project 4- Treatment with Mesothelin CAR T cells
The prognosis for women suffering from advanced ovarian cancer remains poor despite significant progress in the field of gynecological cancer during the last decades. Alternate strategies are required, particularly in patients where conventional therapy has failed and current available standard treatment modalities are exhausted. Epithelial ovarian cancer is the fifth-leading cause of death for women in the developed world; it is also the gynecologic malignancy with highest death rate. Current standard treatment consists of radical surgery in combination with carboplatin and paclitaxel. Even after extensive surgery and chemotherapy, up to 50% of patients suffer from disease recurrence.
Adoptive cell therapy using engineered T cells expressing natural or synthetic receptors for antigen is emerging as a promising strategy to rapidly establish tumor immunity and eradicate small or large tumor burdens. In several CD19 CAR programs, multiple complete remissions in patients with relapsed, chemo-refractory B cell malignancies have been obtained. Given the potential high efficiency of CAR therapy, it is critical to identify appropriate antigens to target in solid tumors, in order to achieve significant tumor eradication with tolerable toxicity to healthy tissues.
Mesothelin (MSLN) is emerging as an attractive target for cancer immunotherapy due to its low expression on normal cells, its expression in a broad spectrum of solid tumors, and the established safety profile of other MSLN-targeted immunotherapies evaluated to date. MSLN is a surface glycoprotein that is anchored to the plasma membrane by a glycophosphatidyl inositol domain. In ovarian cancer, MSLN expression tends to be widespread and homogeneously distributed on the cell surface, with low cytoplasmic expression. Given this pattern of expression, MSLN is an attractive immunotherapeutic target.
In this project, we will 1) evaluate in vitro the functionality of the two human MSLN-directed CAR T cells, 2) establish an orthotopic mouse model of ovarian cancer, 3) evaluate the two different human MSLN CAR T cells in vivo using the orthotopic mouse model of ovarian cancer established in Aim 2. The results obtained will be compared to those obtained in Aim 1, and identify the potential best MSLN CAR construct for clinical trial in patients with advanced ovarian cancer.
Jonas Mattsson, MD, PhD, Senior physician, Professor, Group leader
Mats Remberger, PhD, Professor
Isabelle Magalhaes, PhD, Assistant Professor
Lisa-Mari Mörk, PhD, Laboratory Manager
Ibrahim El Serafi MD, PhD, Post-doc
Johan Karlsson Törlén, MD, PhD student
Esther Schoutrop, MSc, PhD student
Linda Gillingsjö, Administrator
Ola Blennow, MD, PhD, Associated
Anna Nordlander, MD, PhD, Associated
- Karolinska Institutet funds
- Cancerföreningen i Stockholm
- Cancer och Allergifonden
- Belding and Rathsman private donation
- Mix Family private donation
Sofia Berglund “Umbilical cord blood transplantation: clinical outcome, chimerism development, and in vitro expansion of T-cells for clinical use” (2014). Link to the abstract.
Ola Blennow “Diagnostic and clinical aspects of invasive fungal disease after allogeneic hematopoietic stem cell transplantation” (2014). Link to the abstract.
Darius Sairafi ”Methods and biomarkers for outcome prediction after allogeneic hematopoietic stem cell transplantation” (2012). Link to the abstract.
Mantas Okas ”Novel immunotherapeutical strategies in allogeneic stem cell transplantation” (2010). Link to the abstract.
Anna Nordlander ”Alloreactivity in stem cell transplantation” (2008). Link to the abstract.
Marie Jaksch ”Molecular monitoring of acute graft-versus-host disease after allogeneic stem cell transplantation” (2004). Link to the abstract.
Combining Flow and Mass Cytometry in the Search for Biomarkers in Chronic Graft-versus-Host Disease.
Front Immunol 2017 ;8():717
No effect of HLA-C mismatch after allogeneic hematopoietic stem cell transplantation with unrelated donors and T-cell depletion in patients with hematological malignancies.
Clin Transplant 2017 08;31(8):
A prospective randomized trial comparing cyclosporine/methotrexate and tacrolimus/sirolimus as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation.
Haematologica 2016 11;101(11):1417-1425
Effect of Total Nucleated and CD34(+) Cell Dose on Outcome after Allogeneic Hematopoietic Stem Cell Transplantation.
Biol. Blood Marrow Transplant. 2015 May;21(5):889-93
Rapid salvage treatment with virus-specific T cells for therapy-resistant disease.
Clin. Infect. Dis. 2012 Oct;55(8):1064-73