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

Abstract

Background: The 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.

Methods: The 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.

Results: The 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.

Conclusions: We 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.

Keywords: Modified-DCvaccine; Non-small cell lung cancer (NSCLC); Phase I clinical trial.

Fig. 1

Modified-DC vaccination schedule. W, week; IV, intravenous; PBMC, peripheral blood mononuclear cell

Fig. 2

Immunohistochemical expression of survivin and MUC1 in NSCLC [×10]. Survivin and MUC1 staining was carried out in the same NSCLC tumor biopsies. Survivin was expressed mainly in the cytoplasm, and MUC1 was mainly expressed in the membrane. a Patient 9 with squamous cell carcinoma. b Patient 1 with adenocarcinoma. Scale bar: 20 μm

Fig. 3

The phenotypes of Modified-DC (HLA-ABC/HLA-DR/CD80/CD86/ CD40/CD83/CD54/CCR7) by flow cytometry analysis. a The pooled data (n = 15) represents modified-DC phenotypes of pre- and post-culture. Results represent mean ± standard deviation. The cell population with HLA-DR/CD80/CD86/CD40 /CD83/CD54 phenotypein matured modified-DCs were significantly increased compared with pre-culture (n = 15; *, p < 0.05; **, p < 0.01; ***, p < 0.00; NS, no significant); the cell population with HLA-ABC and CCR7 phenotype in matured modified-DCs were decreased compared with pre-culture (n = 15, p < 0.05 and p > 0.05, respectively). b Representative data of different cell populations in matured and pre-cultured DCs

Fig. 4

Lymphocyte subgroups with pre-vaccination (day 0) and post-vaccination (day 14, 21, and 28) as by flow cytometry. a The bar graph represent mean ± standard deviation (n = 15). The percentages of CD3⁺CD4⁺T cells,CD3⁺CD8⁺ T cell, CD3⁺CD56⁺ natural killer T (NKT) cell, CD3⁺Vα24⁺ iNKT cell, and CD3⁻CD16⁺CD56⁺ NK cell populations were not significantly increased (p > 0.05). The percentage of CD3⁺CD4⁺CD25⁺Foxp3⁺ T regulatory cells (Tregs) population was significantly decreased starting from day 14 (*, p < 0.05). b Representative dot plot (gated on CD3⁺CD4⁺CD25⁺) of CD3⁺CD4⁺CD25⁺Foxp3⁺ Tregs of post-and pre-vaccination

Fig. 5

Levels of cytokines IL-2, IL-4, IL-6, IL-10, IFN-γ, and TNF-α. Percentage changes in individual cytokine levels are represented in line graphs (a). Comparisons of the leves of individual patients for TNF-α (b) and IL-6 (c) levels are indicated with respect to time

Fig. 6

Tumor marker expression pre-vaccination at day 0 and post-vaccination at day 14, 21and 28. a The CEA levels under post-vaccination were decreased compared with pre-vaccination in patient 14. b The levels of CYFRA21 had decreased to normal at post-vaccination compared with pre-vaccination in patient 15

Fig. 7

Score of patients’ quality of life. a All enrolled patients (p = 0.003). b Low dose group (p > 0.05). c Middle dose group (p > 0.05). d High dose group (p < 0.05). Each line represents one patient. Pre-Tx, pre-vaccination; Post-Tx,post-vaccination