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- Hjelm Skog, Anna-Lena
(author)
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Monoclonal antibodies and cytokines for therapy of patients with advanced colorectal carcinoma : a clinical and immunological study
- 2000
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Doctoral thesis (other academic/artistic)abstract
- There is a great need for developing and improving treatment alternatives in colorectal carcinoma (CRC). The tumour associated antigen (TAA) GA733/CO17-1A is expressed by more than 90% of all CRCs, on the majority of both primary and metastatic CRC cells. This antigen can be utilised as a target structure for passive as well as active immunotherapy. Mouse MAb17-1A has been produced against this antigen and shown to induce clinical responses in patients. The clinical effect might be improved by adding cytokines, which might augment immune effector functions utilised by MAb. In this study we have analysed clinical and immunological in vivo functions of patients with advanced CRC treated with a combination of the MAb 17-1A, GM-CSF and IL-2. The first analysis concerned the clinical effect of IL-2 alone, without MAb. Low doses of IL-2 were given in combination with IFN-[alpha] to 15 patients with metastatic CRC. No patient showed a major response. Six patients had a stable disease. In the subsequent study the clinical response and immune effector functions were analysed when IL-2 was added to a combination of MAb/GM-CSF, the so far best treatment regimen. 20 patients with metastatic CRC were included in this study. One patient obtained a partial remission and two patients stable disease. The therapeutic effect did not seem to be improved when IL-2 was added to MAb/GM-CSF therapy, which was in contrast to expectations from preclinical data. There might be a tendency to a lower response rate and impaired survival for MAb/GM-CSF/IL-2 treated patients as compared to patients treated with MAb/GM-CSF. When analysing different in vivo effects a suppressed human anti-mouse (HAMA) and antiidiotypic antibody (Ab2) response as well as an impaired antibody dependent cellular cytotoxicity (ADCC) was observed. There was also a tendency to reduction of the frequency and severity of allergic reactions in MAb/GM-CSF/IL-2 treated patients as compared to MAb/GM-CSF treated patients. A highly significant increase in neopterin and sIL-2R serum concentration was noted in the MAb/GM-CSF/IL-2 treatment group as compared to the MAb/GM-CSF group. These data may indicate induction of immune suppression when IL-2 was added to MAb/GM-CSF. Increases in neopterin and sIL-2R concentrations may reflect activation of cellular immune responses mainly involving macrophages and lymphocytes. High concentrations of these serum markers might indicate generation of oxidative stress. Induction of cytokine antibodies has earlier been shown to hamper the clinical responses of biotherapeutic agents. This study revealed differences in immunogenicity between different preparations of GM-CSF and that neutralising anti-GM-CSF antibodies had biological implications. Furthermore, it was obvious that non-neutralising IL-2 antibodies had a profound impact on IL-2 pharmacokinetics. In IL-2 antibody positive patients a decreased cytokine induced increment of leukocytes was observed. As the use of therapeutic cytokines is increasing it seems to be of particular importance to establish the optimal biological doses of different cytokines as well as to carefully evaluate the induction of cytokine antibodies to be able to use cytokines rationally in the clinic.
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| 2. |
- Östergren, Anna, et al.
(author)
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Long-term retention of β-carbolines in brain neuromelanin
- 2004
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In: Journal of neural transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 111:2, s. 141-157
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Journal article (peer-reviewed)abstract
- beta-Carbolines show structural resemblance to the neurotoxic N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and are metabolized to mitochondrial toxicants. Humans are continuously exposed to low levels of beta-carbolines through cooked food, coffee, alcoholic beverages and tobacco smoke. beta-Carbolines have previously been detected in higher levels in the pigmented substantia nigra than in the cortex of humans. The distribution of 3H-labelled harman and norharman in the brain of pigmented and albino mice and in frogs (a species having neuromelanin) was studied by tape-section and light-microscopic autoradiography. Furthermore, the binding of these beta-carbolines to dopamine-melanin and melanin granules from Sepia officinalis was examined. The results revealed a high affinity binding to melanin and a long-term retention (up to 30 days) in pigmented tissues, including neuromelanin-containing neurons of frogs after a single injection. The role of long-term exposure to food-related beta-carbolines and a retention of these compounds in pigment-containing neurons in the induction of idiopathic Parkinson's disease should be further considered.
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