Håkan Mellstedt/Anders Österborg's Group

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Professor, senior

Håkan Mellstedt

Phone: +46-(0)8-517 746 41
Organizational unit: Research Group Mellstedt, Håkan
E-mail: Hakan.Mellstedt@ki.se

The overall objectives are to study: I) natural antitumor immunity in chronic B cell malignancies (myeloma/CLL) and colorectal carcinoma as a basis for identifying target structures for specific immunotherapy (monoclonal antibodies, cancer vaccines) (tumor antigens, which evoke a spontaneous anti-tumor immunity might be of preference to utilize for immuno-therapy); II) characterize immune dysfunctions in cancer patients as a basis for therapeutic inventions with the aim to correct these defects and to select patients which might most benefit from immunotherapy; III) develop therapy with monoclonal antibodies and cancer vaccines to an effective concept in B cell malignancies and colorectal carcinoma.

In myeloma patients, tumor derived immuno-globulin VH-CDRI1 and 111 sequences are targets for natural occurring MW class 1 and II restricted T cells. The idiotype of the tumor derived myeloma protein might thus be a suitable vaccine candidate. CLL patients have monoclonal/oligoclonal expansions of TCRBV populations. They are found within the CD4 as well as CD8 T cell subsets. Studies are in progress to analyze whether these expansions are recognizing the leukemic B cells and which are the recognition structures.

MAb 17-IA is an effective monoclonal antibody for treatment of colorectal carcinoma. Based on pre-clinical studies, addition of GM-CS17 and IL-2 should increase the therapeutic efficacy. However, this was not the case in the clinic but rather the clinical effect was hampered. This might be due to induction of immunesuppression by this specific combination of GM-CSI` and IL-2 as measured by impaired ADCC activity as well as impaired induction of a humoral and cellular idiotypic network response. These findings stress the importance of intense immune monitoring during immunotherapy to understand and interpret obtained clinical results to be able to optimize future therapeutic strategies.

During 1999 the first gene vaccination trial in Sweden started. Patients with colorectal carcinoma stages 11 and 111 are immunized with an avipox viral vector containing the full length gene of the tumor associated antigen GA733. Half of the patients are vaccinated with the vector alone and the other half receive the vector together with local administration of the adjuvant cytokine GM-CSE.

Treatment with cytokines (GM-CSF/IL-2) in non-immunocompromised patients might induced anti-eytokine antibodies, which may hamper the effect of repeated administration of these drugs. This information is of importance for the future development of cytokine treatment strategies to find mean to reduce antibody induction to maintain the effectiveness of the administered cytokine and to avoid morbidity.

Selected publications

Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia.
Wierda W, Kipps T, Mayer J, Stilgenbauer S, Williams C, Hellmann A, et al
J. Clin. Oncol. 2010 Apr;28(10):1749-55

Silencing of ROR1 and FMOD with siRNA results in apoptosis of CLL cells.
Choudhury A, Derkow K, Daneshmanesh A, Mikaelsson E, Kiaii S, Kokhaei P, et al
Br. J. Haematol. 2010 Nov;151(4):327-35

Primary mediastinal B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: results of the Mabthera International Trial Group study.
Rieger M, Osterborg A, Pettengell R, White D, Gill D, Walewski J, et al
Ann. Oncol. 2011 Mar;22(3):664-70

Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study.
Wierda W, Padmanabhan S, Chan G, Gupta I, Lisby S, Osterborg A, et al
Blood 2011 Nov;118(19):5126-9

A novel adoptive transfer model of chronic lymphocytic leukemia suggests a key role for T lymphocytes in the disease.
Bagnara D, Kaufman M, Calissano C, Marsilio S, Patten P, Simone R, et al
Blood 2011 May;117(20):5463-72

Monoclonal antibodies against ROR1 induce apoptosis of chronic lymphocytic leukemia (CLL) cells.
Daneshmanesh A, Hojjat-Farsangi M, Khan A, Jeddi-Tehrani M, Akhondi M, Bayat A, et al
Leukemia 2012 Jun;26(6):1348-55

Epithelial cell adhesion molecule expression (CD326) in cancer: a short review.
Patriarca C, Macchi R, Marschner A, Mellstedt H
Cancer Treat. Rev. 2012 Feb;38(1):68-75

Phase I study of lenalidomide and alemtuzumab in refractory chronic lymphocytic leukaemia: maintaining immune functions during therapy-induced immunosuppression.
Sylvan S, Rossmann E, Mozaffari F, Porwit A, Norin S, Karlsson C, et al
Br. J. Haematol. 2012 Dec;159(5):608-12

Outcomes of patients with fludarabine-refractory chronic lymphocytic leukemia: a population-based study from a well-defined geographic region.
Eketorp Sylvan S, Hansson L, Karlsson C, Norin S, Lundin J, Osterborg A
Leuk. Lymphoma 2014 Aug;55(8):1774-80

The tyrosine kinase receptor ROR1 is constitutively phosphorylated in chronic lymphocytic leukemia (CLL) cells.
Hojjat-Farsangi M, Khan A, Daneshmanesh A, Moshfegh A, Sandin A, Mansouri L, et al
PLoS ONE 2013 ;8(10):e78339