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First-in-human stud...
First-in-human study with intratumoral administration of a CD40 agonistic antibody, ADC-1013, in advanced solid malignancies
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- Irenaeus, Sandra (author)
- Uppsala universitet,Experimentell och klinisk onkologi
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- Nielsen, Dorte (author)
- Herlev Gentofte Hosp, Dept Oncol, Herlev, Denmark
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- Ellmark, Peter (author)
- Medicon Village, Alligator Biosci AB, Lund, Sweden
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- Yachnin, Jeffrey (author)
- Karolinska Institutet
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- Deronic, Adnan (author)
- Medicon Village, Alligator Biosci AB, Lund, Sweden
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- Nilsson, Anneli (author)
- Medicon Village, Alligator Biosci AB, Lund, Sweden
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- Norlen, Per (author)
- Medicon Village, Alligator Biosci AB, Lund, Sweden
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- Veitonmaki, Niina (author)
- Medicon Village, Alligator Biosci AB, Lund, Sweden
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- Wennersten, Camilla S. (author)
- Medicon Village, Alligator Biosci AB, Lund, Sweden
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- Ullenhag, Gustav (author)
- Uppsala universitet,Experimentell och klinisk onkologi
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(creator_code:org_t)
- 2019-03-08
- 2019
- English.
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In: International Journal of Cancer. - : WILEY. - 0020-7136 .- 1097-0215. ; 145:5, s. 1189-1199
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Abstract
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- Agonistic CD40 antibodies activate dendritic cells and can expand and activate tumor-specific T cells. Our purpose was to assess the CD40 agonistic antibody ADC-1013 in the clinical setting including intratumoral administration since preclinical studies have indicated that intratumoral is better than intravenous administration. A Phase I, open label, multicenter study was conducted in patients with advanced solid tumors who had received established treatments. A modified 3 + 3 dose-escalation was applied (every other week dosing). Twenty-three patients were treated with ADC-1013 intratumorally (dosing from 22.5 mu g/kg up to 400 mu g/kg) or intravenously (dosing at 75 mu g/kg). The pharmacodynamic effects observed in the patients were further verified in an hCD40tg mouse model. Adverse events were mostly Common Terminology Criteria for Adverse Events (CTCAE) Grades 1 or 2 and transient. The serum concentration ADC-1013 and cytokine release (MCP-1, TNF alpha and IL-6) were more pronounced in patients receiving injections in deep metastases compared to patients receiving injections in superficial metastases. Treatment with ADC-1013 resulted in a marked decrease in B cell levels in peripheral blood after 24 h while remaining B cells significantly increased their expression of the cell surface activation marker CD86. Activation of antigen-presenting cells and subsequent activation of T cells were demonstrated in hCD40tg mice. Moreover, ADC-1013 treatment in this mouse model acted synergistically with a PD-1 inhibitor. The results from the first-in-human study of ADC-1013 indicate that intratumoral administration of ADC-1013 into superficial lesions is well tolerated at clinically relevant doses and associated with pharmacodynamic responses.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- agonistic antibody
- CD40
- phase I study
- metastatic cancer
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Irenaeus, Sandra
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Nielsen, Dorte
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Ellmark, Peter
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Yachnin, Jeffrey
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Deronic, Adnan
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Nilsson, Anneli
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show more...
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Norlen, Per
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Veitonmaki, Niin ...
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Wennersten, Cami ...
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Ullenhag, Gustav
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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International Jo ...
- By the university
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Uppsala University
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Karolinska Institutet