Lymphoid Malignancies

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, Dr. van de Donk, Dr. Nijhof 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, Dr. Nijhof and 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.

 

Myeloid Malignancies

Research on Myeloid Malignancies in our lab comprises both clinical-translational research and basic-translational research. It is led by a multidisciplinary team of basic scientists (Prof. dr. Cloos, Dr. Smit) and physician scientists (Prof. dr. van de Loosdrecht, Dr. Janssen, and Prof. dr. Ossenkoppele). The research aims at therapeutic target discovery, (pre-)clinical drug development, the identification of biomarkers of therapy response, the design of prognostic models to inform treatment decisions, and the testing of efficacy of novel pharmacological and immunological therapies targeting myeloid neoplasms, with a particular interest in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and chronic myeloid leukemia (CML). The close interaction between basic scientists and clinical researchers guarantees rapid translation of our findings to patients.

We have established a large biobank containing well characterized myeloid leukemia samples to perform ex vivo but also in vivo xenograft mouse model experiments. 

 

Our myeloid research focuses on:

1. Disease monitoring & prognostic modeling

Current projects are on:

  • Improvements on measurable residual disease (MRD) assessment, its implementation as a prognostic factor, as part of clinical decision making and use as an early end point for drug efficacy testing in clinical trials (Prof. dr. Cloos and Prof. dr. Ossenkoppele).

 

2. Therapeutic target discovery and drug resistance

Current projects are on:

  • Characterization of leukemic stem cells (LSC). LSC are thought to initiate relapse, and therefore their elimination will be crucial to prevent recurrence and improve patient outcome. LSC and normal hematopoietic stem cell (HSC) populations are purified from primary patient material and genetically and epigenetically characterized. The results generated are used to guide the rational design of therapeutic strategies that eliminate LSC while sparing HSC (Dr. L. Smit and Dr. J. Janssen).

  • Increasing the knowledge on fundamental mechanisms driving drug resistance and re-initiation of leukemia. Drug resistant human leukemia cells from patients and mouse models are characterized, and subsequently the identified properties are utilized to guide the development of novel therapeutic strategies that overrule drug resistance (Prof. dr. J. CloosDr. L. Smit and Dr. J. Janssen).

 

3. Immune monitoring & immune therapy

Current projects are on:

  • The role of inflammation in MDS pathogenesis. We characterize immune cells and the modulating molecules of the immune system within primary MDS. The identified changes are linked to clinical outcome, and therapeutic options to modulate the identified immune cells and/or associated immune responses are exploited (Prof. dr. A. van de Loosdrecht).

  • Dendritic cell (DC) based immunotherapy. In these projects we aim to activate patient’s cytotoxic T lymphocytes to eradicate MRD in elderly AML patients. Our first vaccine was tested in phase I clinical trial and found safe, feasible and potent in generating cellular and humoral immune responses in patients (Prof. dr. A. van de Loosdrecht).

  • Extensive immunomonitoring in CML aiming at defining predictive parameters for successful tyrosine kinase inhibitor discontinuation (Dr. J. Janssen)

  • CAR-T cell development for AML treatment (Prof. dr. Mutis and Prof. dr. G. Ossenkoppele)

 

Molecular Imaging

The research of the molecular imaging team, led by Prof. dr. Zijlstra, focuses on PET response monitoring in malignant lymphoma and multiple myeloma, and more specific on the value of interim-PET to modify treatment and the use of PET as surrogate endpoint in clinical trials. To this end, Prof dr. Zijlsta and her team have initiated and participate in an international network called PETRA that has been developed to study interim-PET in a broad range of Phase-II and Phase-III clinical trials.

Moreover, using immuno-PET several studies are being performed to elucidate the biodistribution and quantify the effect of therapy of new monoclonal antibodies and antibody drug conjugates.

 

Drug Testing Facility

Our ISO 15189 certified lab has a large biobank containing well characterized primary samples, obtained from patients diagnosed with leukemia, lymphoma or multiple myeloma at different stages of their disease. These samples are instrumental in our preclinical drug development studies, allowing to test the efficacy of new therapies (from small molecules, antibodies to CAR T cells). Within the drug testing facility we investigate the potential of novel therapeutic interventions in close collaboration with our (pharmaceutical) partners. Promising leads from early development or novel utilization of drugs, will be tested in our facility using the following techniques:

  1. in vitro assays, e.g. classical mono-culture and stromal cell co-culture cytotoxicity assays (MTT, AnnexinV-PI, and compartment-specific bioluminescent imaging);

  2. ex vivo assays, e.g. colony-forming unit (CFU) or full BM cytotoxicity assays;

  3. in vivo cell line and patient-derived xenograft (PDX) models in immunocompromised mice (NSG or RAG2-/-gc-/-) or the in-house developed "humanized" BM-like scaffolds (huBMsc) model.

 

Examples of current novel agents under investigation include (but are not limited to):

  • Antibodies: Daratumumab (Janssen Pharmaceutical (J&J), HexaBody-DR5/DR5 (Genmab), Hexabody CD38 (Genmab);

  • Bispecific antibodies: Biclonics CD3xCLEC12A(CLL1) (Merus), DuoBody CD3xCD20 (Genmab), DuoBody CD3xBCMA (Janssen Pharmaceuticals), Duobody CD3xGPRC5D (Janssen Pharmaceuticals);

  • Cellular therapies: CAR T cell development (in house development), CAR NK cell development (Onkimmune), dendritic cell vaccination (in-house development, DCprime);

  • Small molecules: Splicing modulators (H3 Biomedicine), Proteasome inhibitors (Takeda), Liposomal formulations (collaboration prof. dr. R. Schiffelers).

 

In order to efficiently translate our findings to the clinic, our department has a well-established and certified Phase I/II Unit in which we treat patients in investigator initiated (based on own findings) and pharma-sponsored clinical trials.

Examples include (but are not limited to):

  • Phase II: ATRA in EVI-1+ AML patients (Dr. J. Janssen);

  • Phase I/II: Daratumumab in Combination With ATRA in patients with relapsed/refractory multiple myeloma (Dr. N. van de Donk);

  • Phase II: Nivolumab Combined With Daratumumab With or Without Low-dose Cyclophosphamide in patients with relapsed/refractory multiple myeloma (Dr. N. van de Donk).

Finally, our physician scientists lead and participate in large international phase II/III clinical trials through HOVON, European Leukemia Net (ELN), European Myeloma Network (EMN), or pharma-initiated initiatives.

 

Examples include (but are not limited to):

  • Phase II: Hovon 129/EMN 12 study: Carfilzomib and lenalidomide-based treatment for younger and elderly newly diagnosed primary plasma cell leukemia patients;

  • Phase III: Hovon 131/IFM2015-01, Cassipeia: Study of daratumumab in combination with bortezomib, thalidomide, and dexamethasone (VTD) in the first line treatment of transplant eligible subjects with newly diagnosed multiple myeloma;

  • Phase III: Perseus Study (EMN 17): A Phase 3 Study Comparing Daratumumab, VELCADE (bortezomib), Lenalidomide, and Dexamethasone (D-VRd) vs VELCADE, Lenalidomide, and Dexamethasone (VRd) in Subjects with Previously Untreated Multiple Myeloma who are Eligible for High-dose Therapy.

  • Phase III: HOVON 150: multicenter, double-blind, randomized, placebo-controlled study of ivosidenib or enasidenib in combination with induction therapy and consolidation therapy followed by maintenance therapy in patients with newly diagnosed acute myeloid leukemia or myelodysplastic syndrome with excess blasts-2, with an IDH1 or IDH2 mutation, respectively, eligible for intensive chemotherapy.

 

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