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.
Highlights
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 Dendritic cell (DC) produce an unique set of inflammatory factors that recruit and activate non-infected bystander dendritic cells (DCs)
Our findings indicate that intratumoral administration of proinflammatory allogeneic DCs induces an antitumor immune response that may prolong survival in unfavourable risk metastatic renal cell carcinoma (mRCC)-patients given subsequent standard of care
These results reveal that tumor-specific neoantigens are important targets of checkpoint blockade therapy, but can be used to develop personalized cancerspecific vaccines [3]
Summary
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. In a recent phase III trial with the immune checkpoint inhibitor nivolumab (a human monoclonal antibody targeting programmed cell death protein (PD-1)) given to patients with previously treated advanced RCC, overall survival was significantly increased when compared to standard second-line treatment with everolimus [1] Based on these results, nivolumab received approval from the FDA in November 2015 for the treatment of advanced RCC in patients who have received prior antiangiogenic therapy. Mutation-derived and tumor-specific neoantigens are increasingly recognized as immunodeterminants, as there is strong evidence that neoantigen-specific T cells are reactivated, following treatment with checkpoint blockade rendering them capable of mediating tumor rejection [2] These results reveal that tumor-specific neoantigens are important targets of checkpoint blockade therapy, but can be used to develop personalized cancerspecific vaccines [3]. With this type of personalized DC-based vaccines, tumor tissue from each patient is required to identify and prioritize candidate neoantigens, which implicate coordination of tissue acquisition, collection of an autologous leukapheresis product, construction of a vaccine, and administration of the produced vaccine [5]
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