Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer

Abstract

BackgroundDendritic cells (DCs) enhance the quality of anti-tumor immune response in patients with cancer. Thus, we posit that DC-based immunotherapy, in conjunction with toll-like receptor (TLR)-3 agonist poly-ICLC, is a promising approach for harnessing immunity against metastatic or locally advanced unresectable pancreatic cancer (PC).MethodsWe generated autologous DCs from the peripheral blood of HLA-A2+ patients with PC. DCs were pulsed with three distinct A2-restricted peptides: 1) human telomerase reverse transcriptase (hTERT, TERT572Y), 2) carcinoembryonic antigen (CEA; Cap1-6D), and 3) survivin (SRV.A2). Patients received four intradermal injections of 1 × 107 peptide-pulsed DC vaccines every 2 weeks (Day 0, 14, 28, and 42). Concurrently, patients received intramuscular administration of Poly-ICLC at 30 μg/Kg on vaccination days (i.e., day 0, 14, 28, and 42), as well as on days 3, 17, 21, 31, 37, and 45. Our key objective was to assess safety and feasibility. The effect of DC vaccination on immune response was measured at each DC injection time point by enumerating the phenotype and function of patient T cells.ResultsTwelve patients underwent apheresis: nine patients with metastatic disease, and three patients with locally advanced unresectable disease. Vaccines were successfully manufactured from all individuals. We found that this treatment was well-tolerated, with the most common symptoms being fatigue and/or self-limiting flu-like symptoms. Among the eight patients who underwent imaging on day 56, four patients experienced stable disease while four patients had disease progression. The median overall survival was 7.7 months. One patient survived for 28 months post leukapheresis. MHC class I –tetramer analysis before and after vaccination revealed effective generation of antigen-specific T cells in three patients with stable disease.ConclusionVaccination with peptide-pulsed DCs in combination with poly-ICLC is safe and induces a measurable tumor specific T cell population in patients with advanced PC.Trial registration NCT01410968; Name of registry: clinicaltrials.gov; Date of registration: 08/04/2011).Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0459-2) contains supplementary material, which is available to authorized users.

The Toll-Like Receptor 3 Agonist Polyriboinosinic Polyribocytidylic Acid Increases the Numbers of NK Cells with Distinct Phenotype in the Liver of B6 Mice

“…In one of our recent studies, we used the clinical grade (Hiltonol®) of poly(I:C) in a clinical trial of pancreatic cancer to enhance vaccination with DCs loaded with tumour peptides [51]. Hiltonol® was used for the purpose to activate DCs in vitro before loading the peptides as well as in vivo by its administration along with DC vaccine at the vaccination site.…”

Therapeutic Targeting of RIG-I and MDA5 Might Not Lead to the Same Rome

“…A more stable derivative, poly(IC:LC), obtained by modification with poly-L-lysine and carboxymethyl cellulose, has been successfully used in mice for prophylactic and therapeutic protection against a broad spectrum of human viruses including lethal severe acute respiratory syndrome coronavirus (SARS-CoV), lethal H5N1 IAV, and RSV (Table 1) [63][64][65][66]. Incorporating poly(IC:LC) as adjuvant also enhanced the clinical efficiency of experimental vaccines in patients with recurrent malignant glioma, ovarian cancer, or pancreatic cancer [67][68][69]. The undefined structure, heterogeneity, and polydispersity of HMW poly(I:C) and analogs together with unpredictable pharmacokinetics and toxicity, present a hurdle for therapeutic use [4].…”

“…Less than two decades after the first reports characterizing the role of RLRs in immunity, we are closer than ever to having RLR ligands in clinical applications. Pilot trial and ongoing clinical trials in humans are yielding promising results, notably for cancer immunotherapy [67][68][69]85]. Although we have come a long way and key milestones have been reached, there are still significant knowledge gaps that need to be filled by use of molecular, cellular, and structural biology approaches to not only be able to design exclusive and potent RIG-I or MDA5 ligands but also to decide on the most appropriate target for use in antiviral, vaccine adjuvant, or cancer immunotherapeutic applications (see Outstanding Questions).…”

Development of Drugs Based on High-Polymeric Double-Stranded RNA for Antiviral and Antitumor Therapy

“…Studies of biological properties of PolyI: PolyC, started in the 1970s, showed that the drug was a powerful activator of innate immunity and an inducer of tumor cell apoptosis [44]. Promising results have been obtained in clinical studies of PolyI:PolyC as a means of treating seasonal influenza [71], as well as treating malignant tumors of different localizations in adults and children [72][73][74].…”