Karl-Henning Kalland

Karl-Henning Kalland, MD, PhD, has been a professor at the University of Bergen (UiB) since 1993 and serves as a senior consultant at the Department of Microbiology, Haukeland University Hospital, Bergen. Since 2013, he has been the group leader of the Cancer Immunotherapy Research Group and a principal investigator at CCBIO.

Kalland completed his PhD (dr.med.) at UiB in 1989, focusing on the cloning and sequencing of the measles virus and the development of nucleic acid probes. His postdoctoral work at Dana-Farber Cancer Institute, Harvard Medical School, under the invitation of Professor William A. Haseltine, focused on HIV molecular research. 

He continued this research at the UiB through the 1990s. Between 2000 and 2003, Kalland undertook research stays at the University of Washington and the Institute for Systems Biology in Seattle, invited by Professor Leroy Hood, and again at the University of Washington from 2012 to 2013. Recently, he initiated a phase I clinical trial for dendritic cell (DC)-based cryoimmunotherapy (CryoIT) to treat patients with advanced metastatic prostate cancer.

Brief group presentation and history

The Kalland research group was established in the 1980s, initially focusing on the molecular mechanisms of gene regulation using virus-infected cells as models. Significant early contributions include the cDNA cloning and sequencing of the measles virus, RNA editing, and nucleocytoplasmic transport. Major discoveries include RNA editing in the measles virus (PMID: 2789811) and the identification of a nuclear export peptide sequence in HIV-Rev (PMID: 7935458; PMID: 7745679), which revealed novel gene expression mechanisms and provided the first evidence of an active nuclear export signal of proteins.

Around 2000, the group developed a cDNA array platform, as proposed already in 1988 for large-scale transcription monitoring (PMID: 3348914), and later established the Agilent microarray platform to compare gene expression in malignant and benign tissue samples from cancer patients. This work led to collaborations with the Institute for Systems Biology in Seattle and researchers in Bergen, including Professors Lars A. Akslen, Helga Salvesen, Øystein Bruserud, Bjørn Tore Gjertsen and Emmet Mc Cormack, and the bioinformatics group of Professor Inge Jonassen. Through these collaborations, the group identified overexpression of several transcription factors, including ERG and other ETS-family factors (ETV4, ETV5), in prostate cancer tissue compared to benign tissue (PMID: 15645116; PMID: 17143509; PMID: 17289882).

Similar approaches were applied to endometrial cancer biopsies and acute myeloid leukemia samples, identifying malignant gene expression patterns.

Research Focus

• Prostate cell differentiation and carcinogenesis
• Transcriptional regulation and molecular mechanisms in cancer and immune cells
• Developing new drugs and DC-based immunotherapy

Subprojects

1. Experimental Models of Prostate Cell Differentiation and Carcinogenesis:

The aims are to establish experimental models to study prostate cancer differentiation and investigate the molecular mechanisms underlying normal prostate cell
differentiation. Methods include cell cultures of primary prostate cells and cancer cell lines, gene overexpression and knockdown, genome-wide gene expression analyses, and multiple functional assays. The group discovered molecular mechanisms of benign prostate basal to luminal cell differentiation, particularly related to the expression of the androgen receptor (AR) and its target genes. A stepwise prostate tumorigenesis model was developed without carcinogen use, starting from hTERT-immortalized prostate epithelial cells, identifying tumorigenic cells characterized by an IL-6/STAT3 regulatory loop (PMID: 24101153). This model has been used in drug discovery, identifying small molecular compounds that inhibit transcription factors AR, β-catenin, and STAT3.

2. Dendritic Cell (DC)-based Cancer Immunotherapy:

Cancer cell heterogeneity contributes to the failure of drug monotherapy. CryoIT, involving the injection of naïve immature DCs into cryoablated cancer tissue, was hypothesized to address this heterogeneity. The aim of this project is to conduct a phase I clinical trial of CryoIT, with safety as the primary endpoint and evidence of efficacy as the secondary endpoint. Methods include cryoablation of cancer tissue, differentiation of monocyte-derived DCs (moDCs), and analysis of patient samples using clinical biochemistry, pathology, radiology, liquid biopsies, T-cell receptor sequencing (TCR-seq), and CyTOF mass spectrometry. The phase I trial (NCT02423928) showed favorable safety and good patient tolerability. Evidence of therapeutic effects was suggested by circulating tumor cell enumeration and TCR-seq of peripheral blood. As of 2024, 8 of the 18 patients remain alive, with survival times ranging from 4.5 to 9 years.

3. Robust Production of More Potent Therapeutic DCs:

The full potential of DC-based therapy has yet to be realized, and this project aims to investigate mechanisms to enhance pro-inflammatory DCs. Methods include isolation of leukocyte subpopulations, differentiation and maturation of DCs, characterization using RNA-seq, flow cytometry, cytokine and kynurenine secretion, functional assays, and the effects of small molecular compounds on signal transduction pathways. The group discovered that moDCs exhibit both pro-inflammatory and tolerogenic features. They then identified critical gene expression patterns affected by WNT/β-catenin and STAT3 modulators and evaluated conventional DCs as possible replacements for moDCs in future CryoIT.

Translational, clinical, and societal impact

The group’s research has had significant translational and clinical impacts, particularly in cancer treatment:

Clinical impact: The development of CryoIT, a DC-based immunotherapy, has shown promising results in a phase I clinical trial for metastatic castration-resistant prostate cancer, demonstrating prolonged survival and few adverse events. 

Research protocols: Insights from transcription factor studies and prostate cancer models have influenced research protocols and therapeutic strategies.

Societal importance: Advances in cancer immunotherapy have the potential to improve patient outcomes and provide new treatment options. Biomarkers identified in the research are being evaluated for inclusion in clinical trials and practice.

Future perspectives from 2024

Enhance CryoIT: Further to refine and improve DC production and functionality and expand clinical trials to include more cancer types.

Advance biomarker research: Utilize high-resolution sequencing and spatial tissue characterization to better understand and treat cancer.

Innovate cancer therapy: Develop new therapeutic strategies based on the group’s extensive research on transcription factors and molecular mechanisms in cancer.

Expand collaborations: Continue collaborating with international partners to leverage diverse expertise and resources in cancer research and treatment.