1. Monocytes and the bone marrow microenvironment
The bone marrow microenvironment ("niche") plays a decisive role in the regulation of physiological hematopoiesis. A dysfunctional interaction between the niche and hematopoietic stem cells has already been observed in numerous hematologic diseases. While most studies focus on CD45-negative stromal cells as niche cells, hematopoietic stem cells can also influence the composition of the microenvironment by differentiating into monocytes, macrophages and osteoclasts.
Our laboratory is investigating the extent of these hematopoietic cell-induced changes in the micromilieu in myelodysplastic syndromes (MDS). This is done in a mouse model with monocyte-specific reduced expression of PU.1. By means of comprehensive characterization of epigenetic, metabolic and functional peculiarities of niche monocytes, disease-causing mechanisms should be better understood and characterized as possible therapeutic options.
2. Tumor heterogeneity in T-cell lymphomas
Peripheral T-cell lymphomas are very rare lymphoid cancers that exhibit a high degree of heterogeneity. This heterogeneity leads to a subclonal architecture in each cancer patient and could explain acquired treatment failure or relapse over time.
We are performing single-cell RNA analysis on 12 patients with peripheral T-cell lymphoma to identify differences between cancer cells at the transcriptional level. Based on the transcriptional profiles of each cell, we can identify different cell types of the lymph node milieu in each of the 12 patients. To distinguish malignant from non-malignant T cells, we use a bioinformatic tool that can indirectly calculate large copy number variations (CNV) of the individual cells based on RNA expression. As expected, malignant T cells show increased CNVs and divide into several clusters and different subclones. Further analysis of the differential RNA expression and pathway enrichment analyses of the subclones indicate different metabolic dependencies of the subclones. Subsequently, therapeutic weaknesses of these subclones will be identified in order to be able to treat them specifically with a combination therapy.
EXALT-2 (Extended Analysis for Leukemia/Lymphoma Treatment)
Based on the results of the EXALT-1 study (Kornauth C et al., Cancer Discovery, 2022), in which the clinical applicability of precision medicine approaches in advanced hematological diseases was demonstrated, EXALT-2 was developed as a prospective, randomized study with three study arms. It compares two precision medicine approaches (functional drug testing in vitro vs. genetic characterization of the tumor population) against a classical physician's choice control arm. With this design, the EXALT-2 study is a global pioneer in the field of precision medicine and a pioneering project for the integration of these approaches into everyday clinical practice.
Prof. Philipp Staber is currently the principal investigator for 20 clinical trials:
Chronic Lymphocytic Leukemia (CLL):
- CC-122-CLL-001 (Celgene): R/R CLL; Phase 1-2, safety, pharmacokinetics, efficacy
- MOR208C205 (MorphoSys AG): R/R CLL after BTK; Phase 1-2 (national PI)
- CLL13 / DCLSGCLL13001 (GCLLSG): de novo CLL, phase 3
- CLL RT1: Richter's transformation; phase 2 (national PI)
- CLL17 : (GCLLSG): de novo CLL, phase 3 (national PI)
- CLL16 : (GCLLSG): de novo CLL high risk, phase 2 (national PI)
- CC-99282-CLL-00: R/R CLL; (Celgene) phase 1-2, + pharmacokinetics, (institutional PI)
T-cell Lymphomas (T-NHL):
- Ro-CHOP / NCT01796002 (Lysarc): de novo PTCL, phase 3
- ORACLE (Lysarc): de novo AITL, phase 3; start Q9 2019 (national PI)
- VIT study (AbbVie, ITPLLSG): R/R T-PLL, phase 2; start Q4 2019 (international PI)
- AGMT-PTCL registry (MUV): Austrian registry and biobank for T-cell lymphomas
B-cell Lymphomas (B-NHL):
- GO39942 / R-CHP + polatuzumab vedotin (Roche): de novo DLBCL, phase 3
- Chronos 3 / 17067 (Bayer): R/R indolent B-NHL including WM, phase 2 (national PI)
- 1st MIND (MorphoSys AG): de novo DLBCL, phase 1b, start Q1 2020 (national PI)
- Front-Mind (MorphoSys AG): DLBCL, phase 3, placebo-controlled study
- ImbruVeRCHOP in-1st (Charitè Berlin): DLBCL, ibrutinib (Imbruvica®), bortezomib (Velcade®) s.c., Rituximab
NHL/Leukemia:
- EXALT (MUV): 2nd line R/R hem. malignancies, Phase 1 / 2
- EXALT-2 (Roche, MUV): >2nd line R/R hem. malignancies; Phase 3; Q2 2019
- CAR-T:
- Phase 3, Axicabtagene Ciloleucel in High-Risk Large B-Cell Lymphoma (ZUMA-23)
- Phase 2, Brexucabtagene Autoleucel Basket Study in Rare B-cell lymphoma (ZUMA-25)