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.
The Kalland group is focusing on dendritic cell-based cryoimmunotherapy (CryoIT) as a new cancer treatment modality, with integrated drug discovery and development, as their main priorities.
CryoIT: Having completed a phase I clinical trial against metastatic prostate cancer, the group now prepares for the next phase clinical trial. The main efforts in 2021 and beyond are directed towards robust production of potent therapeutic dendritic cells (DCs) in Bergen.
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. Currently, the transcription factors STAT3, androgen receptor (AR), β-catenin and inhibitors of the enzyme Indoleamine 2,3-dioxygenase
1 (IDO1) are investigated.
CryoIT: Good manufacturing practice (GMP)-grade DCs and standard operating procedures are currently established using the Miltenyi CliniMACS Prodigy closed system. The DC product is compared to manually produced monocyte-derived DCs and conventional type 1 (DC1) and type 2 (DC2) which circulate in normal blood. Results that may be very important include the observations that when immature DCs mature in vitro according to widely used routine conditions, proinflammatory and tolerogenic features co-develop. Additionally, in vitro viability of DCs is compromised due to spontaneous apoptosis induction. Molecular and cellular control of such features could generate more potent therapeutic immune cells.
The European Patent Office has approved the patent application of CryoIT combined with intra-tumoral injection of an immune checkpoint inhibitor. The national implementation phase is ongoing. A manuscript reporting the results of the completed phase I clinical trial is still in revision rounds for publication.
Drug Discovery and Development: The group’s repurposing strategy has previously published two compounds that inhibit β-catenin signaling in cancer cell lines. The molecular targets and mechanisms were identified. Novel compounds with STAT3-inhibiting activity have been discovered. One of the compounds exhibited dual inhibition of both androgen receptor (AR) and STAT3. Patent applications have been submitted and licensing is being negotiated with Xennials Therapeutics, Chicago, IL, USA, by Vestlandets Innovasjonselskap (VIS).
The main challenges will be:
- Establishing Good Manufacturing Practice (GMP) grade production of therapeutic dendritic cells in Bergen for the CryoIT next phase clinical trial.
- Revision of the CryoIT protocol with planning and funding of the next phase clinical trial.
- Establishing a new in vivo-mimicking ex vivo-model of patient materials for new quality control tests of therapeutic cells and drug combinations.
The overarching focus and aim will be to develop enhanced immunotherapy against cancer. Kalland envisages a next stage clinical BASKET trial during 2022-2024 and a next generation CryoIT protocol in 2024/25. The BASKET trial will include patients with prostate cancer, kidney cancer and the gynecological vulvar cancer. The next generation CryoIT protocol will be enhanced by more robust and potent therapeutic dendritic cells. Biomarker development and implementation in the next clinical trial includes T-cell receptor sequencing and the in vivo-mimicking ex vivo culture model to assess lymphocyte and dendritic cell functionalities.
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.