Intratumorally injected pro-inflammatory allogeneic dendritic cells as immune enhancers: a first-in-human study in unfavourable risk patients with metastatic renal cell carcinoma

Abstract

BackgroundAccumulating 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.MethodsTwelve 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.ResultsNo 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.ConclusionsOur 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 registrationClinicaltrials.gov identifier: NCT01525017.

Cancer vaccine based on a combination of an infection-enhanced adenoviral vector and pro-inflammatory allogeneic DCs leads to sustained antigen-specific immune responses in three melanoma models

“… 37 Our research findings are also pertinent to the clinical setting, as the alloDCs approach using i.t. injected mature pro-inflammatory alloDCs has already been successfully tested in a phase I/II clinical trial in patients with mRCC 21 and is ongoing in a randomized multicenter phase II study in metastatic RCC patients (NCT02432846).…”

“…Intratumoral administration of pro-inflammatory alloDCs (Ilixadencel) was recently shown to induce an anti-tumor immune response that may prolong survival in unfavorable risk metastatic renal cell carcinoma (mRCC)-patients given subsequent standard of care. 21 Additionally, we have shown that pro-inflammatory, adenoviral-transduced alloDCs created an immunostimulatory environment in vitro , which promoted the maturation of bystander DCs able to cross-present antigens to antigen-specific effector T cells (co-published data). Here, we evaluate alloDCs in combination with an infection-enhanced adenoviral vector in order to load alloDCs with TAAs.…”

Dendritic Cell Cancer Therapy: Vaccinating the Right Patient at the Right Time

“…Clinical studies combining DC vaccination with chemotherapy, radiotherapy, and/or targeted therapy have been performed. Without extensive elaboration on these studies, the safety of combining DC vaccination with these modalities is confirmed in phase I trials ( 97 – 100 ). Futhermore, ample data exist suggesting efficacy ( 101 , 102 ).…”

Integrative characterization and validation of tumor-associated immune signature combined with immune-infiltration analysis in clear cell renal cell carcinoma

“…However, resting mast cells and dendritic cells showed the protective factors in ccRCC, and the dendritic cells was reported as an immune enhancer utilized as baseline in immunotherapy for solid tumors (34,35). What is more, we also used another method to infer the fractions of immune cells based on the characteristic immune cells marker gene (36).…”