Maria Themeli, MD, PhD
Our group’s research interest lies on the field of adoptive immunotherapy with chimeric antigen receptor engineered T cells (CAR T cells). Focusing on the treatment of hematological malignancies such as multiple myeloma (MM), our efforts concentrate on two different but related goals, connected by the global aim of developing next generation cancer immunotherapy with CAR T cells: the broadening of its applicability and the improvement of efficacy and safety.
Generation of functionally mature, histocompatible, “off-the-shelf” CAR T cells.
The development of broadly applicable cellular therapeutics, which have been manufactured, validated and banked in advance, would improve the consistency and availability and reduce the costs of CAR T cell therapy. We have previously shown that T cell-derived induced pluripotent stem cells (TiPSC) have the potential to serve as an unlimited source of functional therapeutic CAR T lymphocytes (Themeli et al. Nat Biotechnol 2013). In addition, TiPSC are an excellent platform for further genetic modifications that would provide their derivatives with optimal properties. We use genetically modified TiPSC as a source of “off-the-shelf” therapeutic T cells with defined and customized characteristics.
Development of novel strategies to improve efficacy and safety of CAR T cell therapy.
We investigate solutions to the bottlenecks of current CAR T cell therapy for MM including downregulation of target expression, loss of CAR T cell persistence and efficacy and specificity of targeting/off-tumor toxicity. Furthermore, we aim to dissect the mechanisms leading to resistance of MM to CAR T cell therapy and investigate the contribution of MM-related, CAR T cell-related as well as BM stroma-related factors to the resistance mechanism.
The Themeli lab is grateful for having received research funding from the Dutch Cancer Society (KWF), Landsteiner Foundation for Blood Transfusion Research, European Commission (Marie Skłodowska-Curie Individual Fellowship, Innovative Medicines Initiative 2), the Multiple Myeloma Research Foundation, VUmc CCA Foundation.
Members of the group
Michail Mamantopoulos PhD | postdoc
Afroditi Katsarou MSc | PhD-student
Alexandros Nianias MSc | PhD-student
Georgios Kladis MSc | PhD-student
Ratchapong Netsrithong | PhD-student
Cindy van Velzen | technician
Dr Themeli studied Medicine in the University of Patras, Greece. After graduating, she did her PhD at the Bone Marrow Transplantation laboratory in the University of Patras Medical School under the supervision of Prof. Alexandros Spyridonidis. During this period she studied the long-term biological consequences of GvHD in epithelial tissues after allogeneic hematopoietic cell transplantation. After completing her PhD training Dr Themeli joined the lab of Dr Michel Sadelain at Memorial Sloan Kettering Cancer Center in New York. There she trained in the design and development of chimeric antigen receptor-engineered T cells (CAR T) and reported for the first time the use of induced pluripotent stem cells (iPSC) as an off-the-shelf source of therapeutic CAR T cells. In 2015 Dr Themeli received a Marie-Curie Individual Fellowship from the European Commission and joined the department of Hematology at Amsterdam UMC-location VUmc, where in 2017 she became Assistant Professor. Dr Themeli has received several prestigious fellowships and awards such as: Clinical Scholars in Biomedical Research Fellowship at MSKCC, NYSCF Druckenmiller fellowship, ASH/EHA TRTH Career development award, Marie Curie individual fellowship from the European Commission and Innovation award from Argo-the Brussels Hellenic Network.
Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy.
Nat Biotechnol. 2013 Oct;31(10):928-33.
Themeli M, Kloss CC, Ciriello G, Fedorov VD, Perna F, Gonen M, Sadelain M.
New cell sources for T cell engineering and adoptive immunotherapy.
Cell Stem Cell. 2015 Apr 2;16(4):357-66.
Themeli M, Rivière I, Sadelain M.
PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses.
Sci Transl Med. 2013 Dec 11;5(215):215ra172.
Fedorov VD, Themeli M, Sadelain M.
Combined CD28 and 4-1BB Costimulation Potentiates Affinity-tuned Chimeric Antigen Receptor-engineered T Cells.
Clin Cancer Res. 2019 Jul 1;25(13):4014-4025.
Drent E, Poels R, Ruiter R, van de Donk NWCJ, Zweegman S, Yuan H, de Bruijn J, Sadelain M, Lokhorst HM, Groen RWJ, Mutis T, Themeli M.
Induced Pluripotent Stem Cell (iPSC)-Derived Lymphocytes for Adoptive Cell Immunotherapy: Recent Advances and Challenges.
Curr Hematol Malig Rep. 2019 Jun 26.
Nianias A, Themeli M.
Combining a CAR and a chimeric costimulatory receptor enhances T cell sensitivity to low antigen density and promotes persistence.
Sci Transl Med. 2021 Dec 8;13(623):eabh1962.
Katsarou A, Sjöstrand M, Naik J, Mansilla-Soto J, Kefala D, Kladis G, Nianias A, Ruiter R, Poels R, Sarkar I, Patankar YR, Merino E, Reijmers RM, Frerichs KA, Yuan H, de Bruijn J, Stroopinsky D, Avigan D, van de Donk NWCJ, Zweegman S, Mutis T, Sadelain M, Groen RWJ, Themeli M.