Comprehensive Cancer Center Freiburg - CCCF

Acute myeloid leukemia (AML) relapse can be cured by an allogeneic hematopoietic cell transplantation (allo-HCT). During allo-HCT, the immune system of a donor is transferred into the patient and can eliminate residual malignant cells (graft-versus-leukemia effect, GVL).  However, immune escape and relapse are the most common cause of death for allo-HCT recipients. The treatment options for relapse are limited, and a second allo-HCT donor is available only for few patients. Therefore, there is a high unmet clinical need to develop novel therapeutic strategies. Based on this situation we are currently conducting the prospective Investigator-initiated trial (IIT) NIFAR "Phase 1/2 Trial to determine the Response Rate of Nivolumab in Acute Myeloid Leukemia (AML) relapse after Allogeneic Hematopoietic Cell Transplantation (allo-HCT)". The study combines the hypomethylating agents (HMA) decitabine or azacitidine with anti-PD-1 immunotherapy. The rationale of the clinical trial is, that administration of the anti-PD-1 antibody nivolumab might enhance alloreactive T cell responses and the GVL effect. Within the scientific program, we would like to study genomic, transcriptomic and phenotypic changes in AML and T cells of the patients during immunotherapy. These changes will be correlated with the patient outcome and clinical parameters to identify predictive factors for response to immunotherapy in allo-HCT recipients.Acute myeloid leukemia (AML) relapse can be cured by an allogeneic hematopoietic cell transplantation (allo-HCT). During allo-HCT, the immune system of a donor is transferred into the patient and can eliminate residual malignant cells (graft-versus-leukemia effect, GVL).  However, immune escape and relapse are the most common cause of death for allo-HCT recipients. The treatment options for relapse are limited, and a second allo-HCT donor is available only for few patients. Therefore, there is a high unmet clinical need to develop novel therapeutic strategies. Based on this situation we are currently conducting the prospective Investigator-initiated trial (IIT) NIFAR "Phase 1/2 Trial to determine the Response Rate of Nivolumab in Acute Myeloid Leukemia (AML) relapse after Allogeneic Hematopoietic Cell Transplantation (allo-HCT)". The study combines the hypomethylating agents (HMA) decitabine or azacitidine with anti-PD-1 immunotherapy. The rationale of the clinical trial is, that administration of the anti-PD-1 antibody nivolumab might enhance alloreactive T cell responses and the GVL effect. Within the scientific program, we would like to study genomic, transcriptomic and phenotypic changes in AML and T cells of the patients during immunotherapy. These changes will be correlated with the patient outcome and clinical parameters to identify predictive factors for response to immunotherapy in allo-HCT recipients.Acute myeloid leukemia (AML) relapse can be cured by an allogeneic hematopoietic cell transplantation (allo-HCT). During allo-HCT, the immune system of a donor is transferred into the patient and can eliminate residual malignant cells (graft-versus-leukemia effect, GVL).  However, immune escape and relapse are the most common cause of death for allo-HCT recipients. The treatment options for relapse are limited, and a second allo-HCT donor is available only for few patients. Therefore, there is a high unmet clinical need to develop novel therapeutic strategies. Based on this situation we are currently conducting the prospective Investigator-initiated trial (IIT) NIFAR "Phase 1/2 Trial to determine the Response Rate of Nivolumab in Acute Myeloid Leukemia (AML) relapse after Allogeneic Hematopoietic Cell Transplantation (allo-HCT)". The study combines the hypomethylating agents (HMA) decitabine or azacitidine with anti-PD-1 immunotherapy. The rationale of the clinical trial is, that administration of the anti-PD-1 antibody nivolumab might enhance alloreactive T cell responses and the GVL effect. Within the scientific program, we would like to study genomic, transcriptomic and phenotypic changes in AML and T cells of the patients during immunotherapy. These changes will be correlated with the patient outcome and clinical parameters to identify predictive factors for response to immunotherapy in allo-HCT recipients.

Hepatocellular carcinoma (HCC) is the major cause of liver cancer and a global health problem, with ~854000 new cases and 810000 deaths in 2018. In early disease stages, liver resection, liver transplant and local ablative therapies can be curative, however, in particular in advanced disease with portal invasion and extrahepatic spread but preserved liver function (Barcelona BCLC stage C), prognosis is limited to 10-16 months despite a growing number of systemic therapy options. Multi-Thyrosinkinase Inhibitors (TKI) Sorafenib, Lenvatinib are options for first line systemic therapies that prolong survival for ~3 months, and Regorafenib, Cabozantinib and anti-VEGFR2 antibody Ramucirumab remain options for 2nd and 3rd line systemic therapy for some patients. Moreover, Stereotactic body radation therapy (SBRT) is frequently used for local tumor control in advanced HCC. HCC can be immunogenic, as indicated by T cell responses against several tumor-associated antigens, such as AFP, Glypican-3, NY-ESO-1, or MAGE-A1/A3, and responses against tumor antigens were linked to better survival. However, only a fraction of ~20% of HCCs falls into an “immune class” with significant enrichment of immune signatures in the tumor. This may explain the insufficient results of anti-PD-1 based immune checkpoint monotherapy phase III trials in HCC (Nivolumab & Pembrozulimab) with about 15-20% ORR. This data is also in line with the immune signatures and transcriptional and mutational landscape in HCC subsets identified in the TCGA consortium with paucity of immune responses in tumors with the frequent TP53, WNT/Catenin mutations. However, recent positive results from a phase III trial with anti-PDL1 and anti-VEGFR combination therapy indicate superiority over TKI treatment with ORR of ~30%, and it is expected that this immunotherapy will be approved by EMA in the next months and become the standard of first line therapy. In line with the poor understanding of the immunobiology of HCC, biomarkers to identify the ~1/3 of patients that will profit from these immunotherapies are currently unknown. Exhausted T cells can be identified in the HCC microenvironment, but their role for patient outcomes and personalized therapy decisions remains unclear.

In this project, we will use our expertise in understanding T cell exhaustion heterogeneity and functional dynamics to identify T cell based predictive biomarkers for HCC outcomes. We will use beyond state-of-the-art methods for the high-dimensional single-cell and spatial profiling of the tumor-immune interaction to stratify HCC patients for personalized immunotherapies.

Our project aims to significantly expand the number of informative mutations in actionable signaling pathways of FGFR, JAK/STAT and BRAF that can support therapy decisions. This will improve the understanding of genomic patient data by functional characterization of uncertain mutations and by incorporating complementary pathway dependencies to choose optimal treatments and to prevent resistance.

This project is performed in close collaboration with Dr. Carla Schmidt (Diederichs lab) and Prof. Dr. Tilman Brummer.

Our research group focuses on the study of clear cell renal cell carcinoma (ccRCC). We study the entire process of tumour formation, beginning with the molecular and cellular mechanisms that underlie the breakdown of normal epithelial proliferative homeostasis, the evolution of tumour cells and parallel evolution of the tumour microenvironment, as well as the process of metastasis. Our major experimental approach is to generate accurate autochthonous mouse tumour models using conventional mouse genetics (Höfflin et al. Nature Communications, 2020; Harlander et al. Nature Medicine 2017; Gonçalves et al Nature Communications 2017, Schönenberger et al. Cancer Research 2016, Guinot et al. Journal of Pathology, 2016, Lehmann et al. JASN, 2015), as well as novel genetic systems that we have developed (Albers et al. JCI, 2015, Brandt et al. Oncotarget 2018, Catalano et al. Cancers 2021). We apply advanced analyses such as RNA sequencing, single cell RNA sequencing, exome sequencing, genome-wide epigenetic analyses, metabolomics, in vivo imaging tools and multi-parametric fluorescence microscopy to our tumour models to gain a broad understanding of disease processes. From the therapeutic perspective, we conduct pre-clinical studies to attempt to uncover specific vulnerabilities of cancer cells that are dictated by their underlying mutational genotype and their microenvironment. Our research in the context of the DKTK aims to develop new personalised therapies that target altered DNA damage signalling and repair networks in ccRCC.

It is widely accepted that cancer - in many cases - is a genetic disease caused by mutations that activate oncogenes and inhibit tumor suppressor genes. However, cancer genetics has mostly focused on "canonical" mutations known to alter the protein like missense or nonsense mutations, deletions or amplifications.

We have found that also other types of mutations, which have so far been overlooked, can have a significant impact on cancer genes - like nonstop extension mutations or synonymous mutations. While they may be less recurrent and more difficult to study, they nonetheless need to be functionally characterized and explored for their impact on patient stratification, where they are currently mostly disregarded.

(EMBO Mol Med 2016, Nat Commun 2019, Nat Cell Biol 2020)