Cancer Cells and Reprogramming Plasticity
Professor Kalland is directing the Prostate Cancer Therapy Research Group at the Department of Clinical Science. The Kalland group pursues a drug discovery and development program and dendritic cell-based cryo-immunotherapy (CryoIT) against cancer.
Drug Discovery and Development: The screening part of this project has utilized both a panel of phytochemicals available in collaboration with Shanghai and a panel of drugs approved for treatment of human and animal diseases according to the repurposing strategy. Luciferase and fluorescent reporter cell lines have been utilized to screen for small molecular compounds that inhibit either β-catenin signaling or STAT3 signaling.
CryoIT: A phase I clinical trial was completed in 2019. The protocol is currently revised in order to conduct next stage clinical trials based upon the important experiences gained regarding safety, treatment effects and biomarkers.
Drug Discovery and Development: The group’s repurposing strategy has identified 2 compounds that inhibit β-catenin signaling in cancer cell lines, and the molecular targets and mechanisms were identified. Further, 3 novel compounds with STAT3-inhibiting activity have been found. Publication is postponed due to the patenting process in collaboration with Shanghai and conducted by VIS (Western Norway Innovation Company).
CryoIT: The Phase I clinical trial was completed in 2019, and 18 patients with metastatic castration-resistant prostate cancer were included. The primary endpoint of safety and patient tolerance appeared very good. Treatment effects were suggested according to radiology, circulating tumor cell enumeration, large-scale serum auto-antibody profiling and ultradeep T-cell receptor sequencing. Patient follow-up is still ongoing. Highly valuable experience has been obtained regarding both treatment aspects and optimized biomarkers that benefit current planning of next generation CryoIT. Results from interim analyses have been presented at international meetings. The comprehensive results are now analyzed and will be published in 2020.
One key focus is the robust production of more potent therapeutic dendritic cells in Bergen for use in next generation CryoIT. In order to achieve this aim, more insight is required into dendritic cell differentiation. The role of β-catenin and STAT3 signaling will be investigated in dendritic cell re-programming in addition to the group’s published results on those pathways in tumor initiating cells. In order to better understand immune cell re-programming in the tissue micro-environment, and the effect of combination therapy, the group aims to establish in vivo mimicking of organoid co-cultures ex vivo. Patient tissue and liquid biopsies will be essential both experimentally and for the development of biomarkers.
Current challenges in the field
Great progress of cancer therapy has been achieved in recent years and continues. Still, increases in median overall survival are mostly measured in months rather than in years in clinical trials with new small molecular compounds. Immune checkpoint inhibitors represent the greatest progress and have achieved long-term and maybe curative effects in subgroups of several cancer types. CAR T-cell therapy has revolutionized treatment of B-cell malignancies and is promising for additional cancertypes. In most cases, however, human cancer is still not curable once it has become metastatic. In the group’s research projects, they envisage potential improvements both in CryoIT with more potent dendritic cells enhanced with new compounds. Biomarker optimization continues for better prediction and monitoring of therapy.
2016 Spring Interview
Professor Kalland is directing the Prostate Cancer Therapy Research Group at the Department of Clinical Science, and the group has made encouraging progress during the last couple of years.
You work with cryoimmunotherapy, can you tell us about your findings?
"Cryoimmunotherapy can theoretically confront the big problem that cancer cells exist as multiple subtypes due to mutations and gene reprogramming. Unfortunately, in invasive cancer there almost always exist cancer cell types that are resistant to any single specific therapy and these cells will cause relapse after seemingly successful initial treatment. In cryoimmunotherapy, immune cells derived from the patient, called dendritic cells, are injected in high numbers into the cancer tissue that first is killed by freezing inside the body. The dendritic cells may then “see” all the different subtypes of cancer cells and instruct the patient’s immune system to attack all those subtypes. Very recently, we have started a Phase I Clinical Trial of cryoimmunotherapy at Haukeland University Hospital."
Can you tell us about your highlights of 2015?
"One highlight in 2015 was that the Phase I Clinical Trial was started and six patients treated before the New Year. It was a lot of work to assemble the clinical teams, establish the logistics and coordinate and conduct the treatments successfully. Another highlight is that our drug discovery and development program, utilizing an experimental prostate cancer model, identified compounds with the ability to block oncogenic signaling. Patent applications have been filed for several compounds with the ability to block the so-called WNT-beta-catenin pathway, and manuscripts reporting molecular targets of the compounds and novel mechanisms are in the publication process."
What are your plans for further research?
"The research biobank associated with the Phase I Clinical Trial, new methodology for monitoring treatment effects and novel leading compounds, have provided a basis for “next generation” immunotherapy. The times are exciting for innovative combinations of immunotherapy and molecular targeted therapy, and we hope to contribute to the cumulative progress within this field."
Find Kalland's PubMed publication list here.