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Intratumorally inje...
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Laurell, AnnaUppsala universitet,Experimentell och klinisk onkologi
(author)
Intratumorally injected pro-inflammatory allogeneic dendritic cells as immune enhancers: a first-in-human study in unfavourable risk patients with metastatic renal cell carcinoma
- Article/chapterEnglish2017
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LIBRIS-ID:oai:gup.ub.gu.se/255700
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https://gup.ub.gu.se/publication/255700URI
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https://doi.org/10.1186/s40425-017-0255-0DOI
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-325567URI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:137552003URI
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
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Background: Accumulating pre-clinical data indicate that the efficient induction of antigen-specific cytotoxic CD8+ T cells characterizing viral infections is caused by cross-priming where initially infected DCs produce an unique set of inflammatory factors that recruit and activate non-infected bystander DCs. Our DC-based immunotherapy concept is guided by such bystander view and accordingly, we have developed a cellular adjuvant consisting of pre-activated allogeneic DCs producing high levels of DC-recruiting and DC-activating factors. This concept doesn't require MHC-compatibility between injected cells and the patient and therefore introduces the possibility of using pre-produced and freeze-stored DCs from healthy blood donors as an off-the-shelf immune enhancer. The use of MHC-incompatible allogeneic DCs will further induce a local rejection process at the injection site that is expected to further enhance recruitment and maturation of endogenous bystander DCs. Methods: Twelve intermediate and poor risk patients with newly diagnosed metastatic renal cell carcinoma (mRCC) where included in a phase I/II study. Pro-inflammatory allogeneic DCs were produced from a leukapheresis product collected from one healthy blood donor and subsequently deep-frozen. A dose of 5-20 x 106 DCs (INTUVAX) was injected into the renal tumor twice with 2 weeks interval before planned nephrectomy and subsequent standard of care. Results: No INTUVAX-related severe adverse events were observed. A massive infiltration of CD8+ T cells was found in 5 out of 12 removed kidney tumors. No objective tumor response was observed and 6 out of 11 evaluable patients have subsequently received additional treatment with standard tyrosine kinase inhibitors (TKI). Three of these 6 patients experienced an objective tumor response including one sunitinib-treated patient who responded with a complete and durable regression of 4 brain metastases. Median overall survival (mOS) is still not reached (currently 42.5 months) but has already passed historical mOS in patients with unfavourable risk mRCC on standard TKI therapy. Conclusions: Our findings indicate that intratumoral administration of proinflammatory allogeneic DCs induces an antitumor immune response that may prolong survival in unfavourable risk mRCC-patients given subsequent standard of care. A randomized, multi-center, phase II mRCC trial (MERECA) with INTUVAX in conjuction with sunitinib has been initiated.
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Lönnemark, MariaUppsala universitet,Radiologi(Swepub:uu)malon030
(author)
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Brekkan, EinarUppsala universitet,Urologkirurgi(Swepub:uu)eibre839
(author)
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Magnusson, Anders,1947-Uppsala universitet,Radiologi(Swepub:uu)anmag679
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Tolf, AnnaUppsala universitet,Klinisk och experimentell patologi(Swepub:uu)annto745
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Wallgren, A. C.Karolinska Inst, Dept Pathol, Stockholm, Sweden
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Andersson, Bengt A.,1952Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för mikrobiologi och immunologi,Institute of Biomedicine, Department of Microbiology and Immunology,Univ Gothenburg, Dept Microbiol & Immunol, Gothenburg, Sweden(Swepub:gu)xabeng
(author)
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Adamson, L.Karolinska Institutet
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Kiessling, R.Karolinska Institutet
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Karlsson-Parra, AlexUppsala universitet,Klinisk immunologi,Immunicum AB, Gothenburg, Sweden(Swepub:uu)aka12694
(author)
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Uppsala universitetExperimentell och klinisk onkologi
(creator_code:org_t)
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In:Journal for Immunotherapy of Cancer: BMJ52051-1426
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Laurell, Anna
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Lönnemark, Maria
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Brekkan, Einar
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Tolf, Anna
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Wallgren, A. C.
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Andersson, Bengt ...
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Adamson, L.
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Kiessling, R.
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