Clinical research on melanoma and breast cancer - QOL, immunology.
Our group focus on translational research, bringing new treatments to patients through novel clinical trials. The focus is primarily on breast cancer and malignant melanoma, and we work broadly from clinical trials, aspects on quality of life, immunology and extra-cellular vesicles.
One example of a current project is the Nivo-ILP trial:
Approximately 5-10% of patients with recurrence of malignant melanoma develop lymphatic dissemination manifested as in-transit metastasis. The most effective treatment is isolated limb perfusion (ILP) with a complete response rate of approximately 60%. During ILP the vasculature of an extremity with tumours is isolated and connected to a heart-lung machine which allows perfusion of the limb with very high doses of the alkylating chemotherapeutic agent melphalan.
This treatment avoids systemic side effects, including toxic effects to the cells of the immune system, while giving a very high regional response rate. Avoiding toxicity to immune cells may be a significant benefit since tumours often decrease gradually during several months after a single ILP treatment.
This clinical observation led to our original hypothesis that the anti-tumoural effect is in part caused by immune-mediated mechanisms. We have shown that ILP causes an up-regulation of tumour specific T-cells, however we have also shown this immunological activation is halted by an up-regulation of PD-1.
Aims of the research
The overall aim is to further expand our knowledge concerning the immunological effects of ILP within a clinical trial combining ILP with a PD-1 inhibitor. We will also use this trial as the framework for a translational project analysing tumour biopsies and blood with methods including advanced patient derived xenograft mouse models, FACS of blood and tumour and multi-colour microscopy techniques.
The specific aims of this study are:
To determine in a clinical trial whether ILP in combination with the checkpoint inhibitor nivolumab significantly increases the complete response rates in melanoma patients with in-transit metastasis.
In previous studies, we have elucidated the immunogenic effects of ILP and have shown that exposure of melanoma cells to melphalan gives rise to an immunogenic type of cell death that triggers dendritic cells and subsequent T cell activation. However, we have also found that the initial stimulation of the immune system triggers an upregulation of PD-1 on activated T cells.
These findings serve as the foundation for the clinical trial “Nivo-ILP” aiming to determine whether the anti-PD-1 immune-checkpoint inhibitor nivolumab can improve the efficacy of ILP treatment even further. The trial is designed as a double-blinded placebo-controlled randomized phase Ib/II trial with complete response rate as the primary endpoint.
To develop an immune-humanized patient derived xenograft (PDXs) platform from patients with in-transit metastases.
We will utilise our clinical trial to create patient derived xenograft models (PDXs) from the samples. We have already developed a new immune-humanized PDX model, termed PDXv2.0 where we have been able to show that the model can predict response to adoptive T cell transfer.
By using the clinical trial as a framework, we will now be able to build a large PDX platform of in-transit metastases, giving us the unique opportunity to further elucidate the immunological effects of ILP and also mimic the trial in a mouse co-clinical trial.
Current group members
Roger Olofsson Bagge, Associate professor, Senior consultant surgeon and group leader at Sahlgrenska Center for Cancer Research and The Wallenberg Center for Molecular and Translational Medicine
Karin Ekström, Senior researcher
Rossella Crescitelli, Senior researcher
Ann-Sophie Lindqvist Bagge, Senior researcher
Anders Carlander, Senior Researcher
Carl-Jacob Holmberg, PhD student
Anna Corderfeldt, PhD student
Nushin Mirzaei, PhD student
Lida Pistioli, PhD student
Marina Modin, Research nurse
Therese Bengtsson, Clinical research coordinator
Désirée Bourghardt Wiklund, Research nurse
Group Roger Olofsson Bagge and its research is affiliated to Sahlgrenska Center for Cancer Research, Wallenberg Centre for Molecular and Translational Medicine as well as the Institute of Clinical Sciences.