The lymphoid malignancies group is led by a multidisciplinary team of basic/translational  scientists (Prof. dr. Mutis, Dr. Groen and Dr. Themeli) and physician scientists (Prof. dr. Zweegman, Prof. dr. van de Donk and Dr. Chamuleau). Our research aims to design novel pharmacological and  immunotherapeutic strategies targeting lymphoid cancers, with a particular interest in multiple myeloma (MM), diffuse large B cell lymphoma and T cell acute lymphoblastic leukemia. To achieve this goal our research is subdivided into different lines in which we investigate several aspects of the pathophysiology of these malignancies.

 

Immunotherapy

One of the main missions of our group is to improve the outcome of lymphoid malignancies through the development and clinical testing of cellular and antibody-based immunotherapies.

 

Cellular immunotherapy (Prof. dr. Mutis and Dr. Themeli)

The primary focus of cellular immunotherapy research program, which is led by Prof. dr. Mutis and Dr. Themeli is the development of safe, effective, affordable available CAR T cell therapies for hematological malignancies through novel strategies, such as

• affinity optimizing of the CARs that are directed of tumor associated antigens;

• development of dual (split) CAR T cell therapies through splitting the first and costimulatory signals of T cell activation among two different CARs;

• combining CAR-T cell therapies with other adoptive cellular therapies.

 

Next to improving the specificity and efficacy of CART cells, one of our ultimate goals is the development of  “off-the-shelf” CAR-T cell therapies that have been manufactured, functionally validated, banked in advance, and can be applied across HLA barriers. To this end, a dedicated team is led by Dr. Themeli, who has specific expertise in induced pluripotent stem cells (iPSC) and have already demonstrated the proof of principle that these cells are excellent unlimited sources to generate therapeutic CAR T lymphocytes.

In our group recognize that another potential off-the-shelf approach could be the engineering of CARs in NK cells, since the administration of  allogeneic NK cells into patients is not associated with a potentially fatal immune complication known as graft-versus-host disease. For this reason,  another team is developing and testing the efficacy of CAR NK cells against MM under supervision of Prof. dr. Mutis, in collaboration with the biotech company Onkimmune.

 

Antibody-based therapies (Prof. dr. Mutis and Prof. dr. van de Donk)

The lymphoid research group has a longstanding expertise in preclinical testing and early clinical evaluation of potentially important antibody-based therapies in collaboration with pharmaceutical companies. To date, we significantly contributed to the development of the FDA approved CD38-specific antibody Daratumumab. Our preclinical analyses not only predicted its single agent activity but also informed on the best combination therapies with Daratumumab, which have recently been successful in clinical trials. Our in-depth analyses of early Daratumumab trials have also revealed unique suppressor-cell depleting activities of Daratumumab.

Building on this knowledge, we are currently investigating the preclinical efficacy of other formats of CD38-antibodies including antibody-immunokine and antibody-drug conjugates. Next to these activities, we utilize similar methodologies for the preclinical evaluation of bispecific antibodies against BCMA, GPRC5 and against CD20, as well as novel hexabody forming antibodies targeting CD38, DR5 and CD37.

 

Bone marrow microenvironment induced therapy resistance (Prof. dr. Mutis and Dr. Groen)

​Many experimental agents deemed promising in preclinical studies have not lived up to these expectations when studied in clinical trials. This discordance between preclinical vs. clinical efficacy may in part be due to the protection conferred to tumor cells by nonmalignant cells of the bone marrow (BM), such as BM stromal cells (BMSCs). This protection is not simulated in conventional screens of tumor cell monocultures in vitro or non-orthotopic (e.g. subcutaneous) xenograft models in vivo. Thus, our group utilizes compartment-specific in vitro stroma-MM cell co-culture models as well as a unique "humanized" BM-like scaffold (huBMsc) model developed by Dr. Groen, to optimally study the impact of the tumor (BM) microenvironment on tumor progression and  treatment response. We also utilize these models to inform the design of novel combinations of pharmacological and immune therapies (e.g. daratumumab combination therapy) and to understand the mechanisms and optimally modulate the microenvironment-mediated therapy resistance (e.g. combination immunotherapy with survivin/MCL-1 inhibitors)

 

MM-induced osteolytic bone disease (Prof. dr. Zweegman and Dr. Groen)

Despite the advances made in the treatment of MM, substantially improving the outcomes in patients with MM, the disease remains incurable. Up to 90% of MM patients develop cancer-induced bone disease throughout the course of their disease. MM-induced bone disease is a result of decreased osteoblastic activity (i.e. differentiation of BMSCs towards mature osteoblasts) and increased osteoclastic activity (i.e. bone resorption). Recently, using the huBMsc model we have characterized the molecular impact of MM cells on osteogenic differentiation and confirmed established disease biomarkers as well as identified novel mediators of MM disease progression and bone disease. The functional and therapeutic implications of these MM-induced changes in stromal cells, we are currently investigating using genetically manipulated iPSC lines that are differentiated into stromal cells.

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