Group Kristoffer Hellstrand

Research summary

Relapse after the completion of induction and consolidation chemotherapy in acute myeloid leukemia (AML) is a significant reason why only approximately 30% of adult AML patients survive beyond five years after diagnosis. Apart from allogeneic stem cell transplantation there is no consensus about relapse-protective therapy in the post-consolidation phase and the standard of care for most patients hence is no treatment.

Immunotherapy with histamine dihydrochloride

Our group has developed immunotherapy with histamine dihydrochloride (HDC) to counteract leukemia-related immunosuppression in AML and hence to ameliorate the efficiency of other immunotherapies, including interleukin-2 (IL-2).

The immunostimulatory features of HDC are assumed result from inhibition of the formation of reactive oxygen species (ROS) by several types of myeloid cells. By diminishing the availability of extracellular ROS, HDC provides a reduced environment suitable for optimal survival and function of anti-leukemic lymphocytes. HDC and IL-2 synergistically activate T- and NK-cell functions in the presence of normal and malignant myeloid cells; in this immunosuppressive microenvironment, the efficiency of IL-2 alone is strongly reduced.

These findings formed the background to the introduction of HDC/IL-2 as a strategy to prevent relapse of AML. A randomized phase III trial with 320 patients in the post-chemotherapy phase demonstrated a sustained and significant reduction of relapse risk after immunotherapy with HDC + low-dose IL-2, which was approved for use within the EU in 2009 and became available for AML patients in Europe in 2010. HDC/IL-2 is the first approved therapeutic to reduce the incidence of relapse in the post-chemotherapy phase of AML.

Two new indications

We will evaluate the potential benefit of HDC/IL-2 in two new indications. In cooperation with the Karolinska Hospital, we will assess clinical and immunomodulatory effects of treatment with HDC/IL-2 + nivolumab in patients with metastatic cancer who have failed to respond to checkpoint inhibitor therapy (NIVOCEP trial). In the PANCEP trial, patients with resectable pancreatic cancer will receive pre- and postoperative HDC/IL-2 aiming to reduce the risk of distant metastasis.

Research tools and resources

The clinical trials are performed at the Sahlgrenska University Hospital (PANCEP trial) and the Karolinska Hospital (NIVOCEP trial). Contemporary aspects of cellular immunity are analysed at the TIMM Laboratory at Sahlgrenska Cancer Center.

Current group members

Kristoffer Hellstrand, MD, PhD, Professor

These studies are performed in collaboration with:

• Anna Martner and Fredrik Bergh Thorén at the TIMM Laboratory
• Mats Brune - Department of Hematology, University of Gothenburg
• Peter Naredi - Department of Surgery, University of Gothenburg
• Jeffrey Aychnin - Department of Oncology, Karolinska Hospital
• Svein Olaf Bratlie - Department of Surgery, University of Gothenburg

Selected publications

1. Complete remission after the first cycle of induction chemotherapy determines the clinical efficacy of relapse-preventive immunotherapy in acute myeloid leukaemia.
   Nilsson MS, Hallner A, Brune M, Nilsson S, Thorén FB, Martner A, Hellstrand K. Br J Haematol, 2019 in press.
    
2. NOX2 inhibition reduces oxidative stress and prolongs survival in murine KRAS-induced myeloproliferative disease.
   Aydin E, Hallner A, Grauers Wiktorin H, Staffas A, Hellstrand K, Martner A. Oncogene 2018 doi: 10.1038/s41388-018-0528-1.
    
3. Role of NOX2-derived reactive oxygen species in NK cell-mediated control of murine melanoma metastasis.
   Aydin E, J Johansson, FH Nazir, K Hellstrand, A Martner. Cancer Immunol Res 2017 5:804-11.
    
4. Impact of killer-immunoglobulin-like receptor and human leukocyte antigen genotypes on the efficacy of immunotherapy in acute myeloid leukemia.
   Bernson E, A Hallner, F Ewald Sander, O Wilsson, O Werlenius, A Rydström, R Kiffin, M Brune, R Foà, J Aurelius, A Martner, K Hellstrand, FB Thorén. Leukemia 2017 31:2552-9.
    
5. Role of natural killer cell subsets and natural cytotoxicity receptors for the outcome of immunotherapy in acute myeloid leukemia.
   Martner A, Rydström A, Ewald F, Riise RE, Aurelius J, Anderson H, Brune M, Foà R, Hellstrand K, Thorén FB for the Re:Mission Study Group. Oncoimmunology 2016 5:5(1):e1041701.
    
6. Histamine promotes the development of monocyte-derived dendritic cells and reduces tumor growth by targeting the myeloid NADPH oxidase.
   Martner A, Wiktorin HG, Lenox B, Ewald Sander F, Aydin E, Aurelius J, Thorén FB, Ståhlberg A, Hermodsson S, Hellstrand K. J Immunol 2015 194:5014-21
    
7. Remission maintenance in acute myeloid leukemia: impact of functional histamine H2 receptors expressed by leukemic cells.
   Aurelius J, Martner A, Brune M, Palmqvist L, Hansson M, Hellstrand K, Thoren FB. Haematologica 2012 97:1904-8.
    
8. Monocytic AML cells inactivate antileukemic lymphocytes: role of NADPH oxidase/gp91(phox) expression and the PARP-1/PAR pathway of apoptosis.
   Aurelius J, Thorén FB, Akhiani A, Brune M, Palmqvist L, Hansson M, Hellstrand K, Martner A. Blood 2012 119:5832-7.
    
9. Redox remodeling by dendritic cells protects antigen-specific T cells against oxidative stress.
   Martner A, Aurelius J, Rydström A, Hellstrand K, Thorén FB. J Immunol 2011 187:6243-8.

More group Kristoffer Hellstrand publications on PubMed