Phase I clinical trial of a novel autologous modified-DC vaccine in patients with resected NSCLC

Abstract

BackgroundThe primary aim of this study was to evaluate the safety of a novel dendritic cell (DC) vaccine pulsed with survivin and MUC1, silenced with suppressor of cytokine signaling 1 (SOCS1), and immune stimulated with flagellin for patients with stage I to IIIA non-small cell lung cancer (NSCLC) in a phase I open-label, uncontrolled, and dose-escalation trial. Moreover, we evaluate the potential efficacy of this modified DC vaccine as secondary aim.MethodsThe patients were treated with the vaccine at 1 × 106, 1 × 107and the maximum dose 8 × 107 at day 7, 14, and 21 after characterization of the vaccine phenotype by flow cytometry. The safety of the vaccine was assessed by adverse events, and the efficacy by the levels of several specific tumor markers and the patient quality of life.ResultsThe vaccine was well tolerated without dose-limiting toxicity even at higher doses. The most common adverse event reported was just grade 1 flu-like symptoms without unanticipated or serious adverse event. A significant decrease in CD3 + CD4 + CD25 + Foxp3+ T regulatory (Treg) cell number and increase in TNF-α and IL-6 were observed in two patients. Two patients showed 15% and 64% decrease in carcino-embryonic antigen and CYFRA21, respectively. The vaccination with the maximum dose significantly improved the patients’quality of life when administered at the highest dose. More importantly, in the long-term follow-up until February 17, 2017, 1 patient had no recurrence, 1 patients had a progressive disease (PD), and 1 patient was died in the low dose group. In the middle dose group, all 3 patients had no recurrence. In the high dose group, 1 patient was died, 1 patient had a PD, and the other 7 patients had no recurrence.ConclusionsWe provide preliminary data on the safety and efficacy profile of a novel vaccine against non-small cell lung cancer, which was reasonably well tolerated, induced modest antitumor activity without dose-limiting toxicity, and improved patients’ quality of life. Further more, the vaccine maybe a very efficacious treatment for patients with resected NSCLC to prevent recurrence. Our findings on the safety and efficacy of the vaccine in this phase I trial warrant future phase II/III clinical trial.

Impaired dendritic cell functions in lung cancer: a review of recent advances and future perspectives

“…Additionally, suppressor of cytokine signal 1 (SOCS1) [106] was also used in this system due to its essential role in negative regulation of DC differentiation and antigen presentation. After DC vaccine treatment, the expression of tumor markers was significantly reduced and the living quality of all patients was improved [107]. In another clinical trial, DCs were transduced with an adenoviral vector expressing C–C motif chemokine ligand 21 (CCL21), which attracts DCs and T cells by interacting with C–C motif chemokine receptor 7 (CCR7) and C-X-C motif chemokine receptor 3 (CXCR3) receptors, recruits antigen-stimulated DCs into T-cell zones in secondary lymphoid organs, and plays a key role in T-cell activation.…”

Dendritic cells pulsed with placental gp96 promote tumor-reactive immune responses

“…g ., mutated neoantigens, cancer germline proteins, and viral proteins) and tumor-associated antigens (TAAs) that are encoded by tissue-specific genes but over-expressed in tumor cells These antigens are loaded on DCs in the form of synthetic peptides, tumor-derived exosomes, autologous or allogeneic cell lysates from killed tumor cells or immunogenic cell death, or by transfecting DCs with tumor-derived whole RNA or DNA [4–7]. Presently, a limited repertoire of cancer antigens for DC loading has been identified to be immunogenically efficient that could elicit an immune response and result in tumor eradication, such as MAGE antigens, gp100, α-fetoprotein (AFP), glypican-3 (GPC-3), Wilms tumor 1, NY-ESO-1, MUC1, and mutated neoantigens [1, 4, 8]. In addition, DC adjuvants are also key to induce DC maturation and activation and, thus, intensify the immune response.…”

TLR4 signaling improves PD-1 blockade therapy during chronic viral infection

“…LPS-activated DCs also synergized with PD-1 therapy and were substantially safer. DC immunotherapy has been used previously in clinical trials to revert CD8 T cell exhaustion, but it has not shown significant clinical benefits [46–49]. Our studies are novel, because we show for the first time that DC immunotherapy using LPS-activated DCs improves the efficacy of PD-1 therapy.…”