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

Immunohistochemical expression

Immunohistochemical expression

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Summary

The 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). The result shows that the treatment is reasonably well tolerated, induced modest antitumor activity, and improved patients’ quality of life. Further more, the vaccine maybe a very efficacious treatment for patients with resected NSCLC to prevent recurrence.

Patients characteristics

15 patients with resected stage I to IIIA NSCLC with median age of 50 years old (range from 40- 61 years old), with an Eastern Cooperative Oncology Group performance status of 0 or 1; life expectancy more than 6 months; adequate bone marrow function, liver and renal function.

Methodology

DCs were generated from peripheral blood mononuclear cells (PBMCs) from each patient using the Cobe Spectra Apheresis System. PBMCs were cultured for six days in serum-free, GMP (Good Manufacturing Practice) certified medium supplemented with granulocyte-macrophage colony- stimulating factor (GM- CSF) and interleukin-4 (IL-4) to obtain immature dendritic cells (iDC).
The PBMCs were isolated by leukapheresis and then re-suspended in serum-free media at 37 °C in a humidified 5% CO2/95% air incubator. After incubation for half an hour, non-adherent cells were removed, and the adherent cells were cultured in media supplemented with 30 ng/mL recombinant human interleukin 4 (IL-4), 100 ng/mL recombinant human granulocyte macrophage- colony stimulating factor (GM-CSF), and 2% human serum albumin and 2 mmol/L glutamine for 6 days. Fresh media supplemented with the cytokine were added every other day. Then iAPA cytokine (10,000 vp/cell) that includes SOCS1-specific small interfering RNA and peptides for Flagellin, survivin, and MUC1 were added to the culture at day 6. The cultured DCs were harvested by vigorous washing with sterile 0.9% NaCl solution at day 7. The matured DCs were confirmed using flow cytometry analysis before vaccination were harvested, washed and re-suspended in 100 mL of sterile 0.9% NaCl solution containing 1% serum albumin.

Treatment

Patients were intravenously injected with 1 × 106, 1 × 107 and the maximum dose DC vaccine suspended in 100 mL of sterile 0.9% NaCl solution containing 1% serum albumin at day 7, 14 and 21, respectively. Dose escalation proceeded using a 3 + 3 cohort design. First, according to eligibility criteria, 3 patients were enrolled and divided into low dose groups, who were
intravenously injected with 1 × 106 DC vaccine. Adverse events (AEs) were observed at 0, 0.5, 1, 1.5, 2, 4, 6, 12, 24, 48, and 72 h after each injection. If there were no unanticipated or serious adverse events occurred in the 28-day period, 3 another patients were enrolled into the middle dose group for 1 × 107 DC vaccine. AEs were also observed, and if there were no unanticipated or serious adverse events, then enrolled 9 patients into the high dose group for the maximum dose DC vaccine.

Results

safety and toxicity
Dose-limiting toxicity was not observed by vaccination with the modified-DC vaccines. The most common adverse events (AEs) were grade 1 flu-like symptoms which did not require any intervention, including pyrexia (40%), fatigue (33.33%), C-reactive protein (CRP) increased (46.67%), myalgia (40%), abdominal pain (33.33%), and nausea (20%). Pyrexia and myalgia commonly occurred in the group immunized with the maximum amount of the vaccine in 5 of 9, and 4 of 9 patients, respectively. One of the patients in the maximum amount vaccine immunized group developed the Grade 1 pyrexia and had the highest temperature 38.9 °C within 4 to 10 h, but the temperature decreased to normal levels within 10 to 20 h after the vaccine infusion. No unanticipated or serious adverse events occurred in the 28-day period.
Clinical response
The tumor markers CEA, SCC, CYFRA21, and CA125 were analyzed in all the patients.13 patients had normal tumor markers at baseline, and only 2 patients had abnormal tumor markers. The carcinoembryonic antigen (CEA) levels were decreased in one patient and the CYFRA21 levels were decreased to normal levels in other one patient after the vaccination. The other tumor markers remained almost at normal levels. Meanwhile, the patients’ quality of life improved after the vaccination as the score of the quality of life was significantly decreased, compared to pre- vaccination. Furthermore, patients’ quality of life was significantly improved in the high-dose group, compared with low- dose and middle-dose groups after the treatment.
More importantly, in the long-term follow-up until 2017(4 years since the start of trial), 1 patient had no recurrence, 1 patient had a progressive disease (PD), and 1 patient was died on May 1, 2015 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 on 21 April, 2015, 1 patient had a PD, and the other 7 patients had no recurrence.

Conclusion

This 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. Furthermore, the vaccine maybe a very efficacious treatment for patients with resected NSCLC to prevent recurrence.

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Scientific article publishing date :12/21/2017

Immucura identifier BSC21_194EN

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