TY - JOUR T1 - Intratumorally injected pro-inflammatory allogeneic dendritic cells as immune enhancers: a first-in-human study in unfavourable risk patients with metastatic renal cell carcinoma JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1186/s40425-017-0255-0 VL - 5 IS - 1 SP - 52 AU - Anna Laurell AU - Maria Lönnemark AU - Einar Brekkan AU - Anders Magnusson AU - Anna Tolf AU - Anna Carin Wallgren AU - Bengt Andersson AU - Lars Adamson AU - Rolf Kiessling AU - Alex Karlsson-Parra Y1 - 2017/12/01 UR - http://jitc.bmj.com/content/5/1/52.abstract N2 - 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 × 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 anti-tumor 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.Trial registration Clinicaltrials.gov identifier: NCT01525017.Abbreviations:CTCCommon Toxicity CriteriaCTLCytotoxic T cellDCDendritic cellECOGEastern Cooperative Oncology GroupELISpotEnzyme-Linked Immunosorbent SpotGM-CSFColony-stimulating factorIFN-γInterferon gammaMLRMixed leucocyte reactionmOSMedian overall survivalmRCCMetastatic renal cell carcinomaNK cellNatural killer cellPBMCsPeripheral blood mononuclear cellsPD-1Programmed cell death proteinPD-L1Programmed cell death ligandRECISTResponse Evaluation Criteria In Solid TumorsTKITyrosine kinase inhibitorTLRToll-like receptor ER -