Jonas Mattsson's Group

Optimization of allogeneic stem cell transplantation and immunotherapy of cancer

Project 1- Randomized study comparing haploidentical donors with matched unrelated donors in patients with AML

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.

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- 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. Complete remission after CD19 CAR treatment in different trials has been reported in 70-90% of patients with ALL, but the efficacy appears more limited in patients with chronic lymphocytic leukemia (CLL). For instance, in CLL the hypoxic conditions in the tumor environment alter T cell metabolism and subsequently the T cells’ effector functions.

We are exploring the impact of the immunosuppressive tumor environment on T cells expressing an anti-CD19 CAR, and particularly the metabolism of CD19 CAR T cells. The aim is to define in vitro culture conditions that allow the production of CD19 CAR T cells that are more fit to function and counteract in vivo the tumor environment encountered in CLL patients.

Project 3- 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. Our group has established an orthotopic mouse model of ovarian cancer.

In this project, we will 1) evaluate in vitro the functionality of the two human MSLN-directed CAR T cells, 2) evaluate the two different human MSLN CAR T cells in vivo using an orthotopic mouse model of ovarian cancer, 3) optimise the conditioning regimen, 4) evaluate potential combination therapies, and 5) identify optimised culture conditions for the production of MSLN-CAR T cells able to withstand the challenging tumor environment.

Our final aim is that the preclinical work will lead to a clinical study in patients with advanced ovarian cancer. This treatment modality could, if proven effective, also be used in a wide range of different cancers expressing MSLN.

Group members

Jonas Mattsson, MD, PhD, Senior physician, visiting Professor, Group leader
Isabelle Magalhaes, PhD, Associate Professor, Senior Researcher, Deputy Group leader
Ibrahim El Serafi MD, PhD, Assistant Professor
Thomas Poiret, PhD, Associated
Sofia Berglund, MD, PhD, Associated
Esther Schoutrop, MSc, PhD student
Isabella Micallef Nilsson, MD, PhD student
Johan Karlsson Törlén, MD, PhD, associated
Linda Gillingsjö, Administrator

Research funding

  • Vetenskapsrådet
  • Cancerfonden
  • Cancerföreningen i Stockholm
  • Barncancerfonden
  • Dr Åke Olssons stiftelse
  • Svenska Läkaresällskapet
  • Stiftelsen Clas Groschinskys Minnesfond
  • Karolinska Institutet funds
  • Belding and Rathsman private donation
  • Mix Family private donation
  • KID funding
  • Kungl. Vetenskapsakademien
  • Cancer och allergifonden
  • Stiftelsen Tornspiran

Dissertations

Johan Karlsson Törlén “From risk indices to reconstitution of immunity: Studies of outcome-related factors in patients undergoing allogeneic hematopoietic stem cell transplantation” (2019). Link to the abstract.

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.

Selected publications

Mesothelin-specific CAR T cells target ovarian cancer.
Schoutrop E, El-Serafi I, Poiret T, Zhao Y, Gultekin O, He R, Moyano-Galceran L, Carlson JW, Lehti K, Hassan M, Magalhaes I, Mattsson J
Cancer Res 2021 Apr;():

Reduced Risk of Sinusoidal Obstruction Syndrome of the Liver after Busulfan-Cyclophosphamide Conditioning Prior to Allogeneic Hematopoietic Stem Cell Transplantation.
El-Serafi I, Remberger M, Ringdèn O, Törlén J, Sundin M, Björklund A, Winiarski J, Mattsson J
Clin Transl Sci 2020 03;13(2):293-300

Pre-formulation investigations for establishing a protocol for treosulfan handling and activation.
El-Serafi I, Loy O, Zhao Y, Oerther S, Mattsson J
Pharm Dev Technol 2019 Jun;24(5):639-648

The effect of N-acetyl-l-cysteine (NAC) on liver toxicity and clinical outcome after hematopoietic stem cell transplantation.
El-Serafi I, Remberger M, El-Serafi A, Benkessou F, Zheng W, Martell E, Ljungman P, Mattsson J, Hassan M
Sci Rep 2018 05;8(1):8293

Mesothelin Expression in Patients with High-Grade Serous Ovarian Cancer Does Not Predict Clinical Outcome But Correlates with CD11c+ Expression in Tumor.
Magalhaes I, Fernebro J, Abd Own S, Glaessgen D, Corvigno S, Remberger M, et al
Adv Ther 2020 12;37(12):5023-5031

The Metabolic Profile of Tumor and Virally Infected Cells Shapes Their Microenvironment Counteracting T Cell Immunity.
Magalhaes I, Yogev O, Mattsson J, Schurich A
Front Immunol 2019 ;10():2309

Facing the future: challenges and opportunities in adoptive T cell therapy in cancer.
Magalhaes I, Carvalho-Queiroz C, Hartana CA, Kaiser A, Lukic A, Mints M, et al
Expert Opin Biol Ther 2019 08;19(8):811-827

Metabolic regulation of CAR T cell function by the hypoxic microenvironment in solid tumors.
Schurich A, Magalhaes I, Mattsson J
Immunotherapy 2019 03;11(4):335-345

Media evaluation for production and expansion of anti-CD19 chimeric antigen receptor T cells.
Alnabhan R, Gaballa A, Mörk LM, Mattsson J, Uhlin M, Magalhaes I
Cytotherapy 2018 07;20(7):941-951

CD19 Chimeric Antigen Receptor T Cells From Patients With Chronic Lymphocytic Leukemia Display an Elevated IFN-γ Production Profile.
Magalhaes I, Kalland I, Kochenderfer JN, Österborg A, Uhlin M, Mattsson J
J. Immunother. ;41(2):73-83

A prospective randomized trial comparing cyclosporine/methotrexate and tacrolimus/sirolimus as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation.
Törlén J, Ringdén O, Garming-Legert K, Ljungman P, Winiarski J, Remes K, et al
Haematologica 2016 11;101(11):1417-1425

Effect of Total Nucleated and CD34(+) Cell Dose on Outcome after Allogeneic Hematopoietic Stem Cell Transplantation.
Remberger M, Törlén J, Ringdén O, Engström M, Watz E, Uhlin M, et al
Biol. Blood Marrow Transplant. 2015 May;21(5):889-93

Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation.
Uhlin M, Wikell H, Sundin M, Blennow O, Maeurer M, Ringden O, et al
Haematologica 2014 Feb;99(2):346-52

Visiting address:

Karolinska Institutet Campus Flemingsberg
ANA Futura, 7th floor
Alfred Nobels allé 8 Huddinge