Ad.p53-DC vaccine was produced using 1 to 2 blood volumes leukapheresis product that was obtained through Cobe Spectra hemapheresis units. The cell product underwent an automated Ficoll separation and was stored at –96°C in a 150 mL volume of plasmalyte-A/20% autologous plasma solution with 10% dimethyl sulfoxide. The cells were thawed approximately 1 week prior to vaccination, washed in Cell Genix DC medium, and then adherent DC cells were incubated in tissue culture flasks and activated with 100 ng/mL granulocyte-macrophage colony-stimulating factor and 50 ng/mL interleukin 4 over 4 days. Following activation, the DCs were infected with Ad.p53 at a multiplicity of infection of 15 000 particles per cell and incubated for 48 hours.
The final volume (1mL, 1–5 × 106 p53+ DC cells) of Ad.p53-DC vaccine was administered intradermally as 4 × 0.25 mL doses distributed over the right and left axillary and inguinal lymphatic basins once every 2 weeks over a 6-week period.
Indoximod (50 mg and 200 mg hard gelatin capsules) was administered orally twice daily on an empty stomach for 21-day continuous cycles. Patients took indoximod throughout the entire vaccination series and as monotherapy thereafter, if they continued to demonstrate clinical benefit.
The grade 5 dyspnea was a respiratory failure event, which was due to disease progression. The most common grade 1 to 2 adverse events (occurring more than 20% of patients) possibly related to study therapy were fatigue, anemia, transient lymphopenia, nausea, and anorexia. None ofthe toxicities required treatment discontinuation, and the study treatment was well tolerated overall.
No dose-limiting toxicities were encountered during the therapy, and the study eventually reached the maximum- recommended phase-2 dose for indoximod of 1600 mg, administered orally twice a day, in combination with the Ad.p53-DC vaccine.
The best observed responses, as measured by Response Evaluation Criteria in Solid Tumors (RECIST), were 4 patients with stable disease at week 7. No objective responses were observed during the vaccination treatment period in phase1-or 2-enrolled patients. Of the 39 treated patients, 22 patients were able to go onto at least 2 cycles of subsequent post vaccination therapy and be evaluated for response by their treating physicians. The remainder experienced significant declines due to disease progression and were enrolled in palliative care. The regimens included gemcitabine, carboplatinum/ gemcitabine, eribulin, and navelbine. Nine of the 22 patients (40%) had either stable disease (SD) or better on imaging (1 complete response, 7 partial responses, 1 stable disease).
The median progression-free survival (PFS) for the enrolled study population was 13.3 weeks (95% CI, 12.97–21.85) and median overall survival (OS) was 20.71 weeks (95% CI, 25.75–46.15). In the 9 patients who attained a response to salvage chemotherapy following study treatment, the median overall survival was 69.4 weeks (95% CI, 30.1–122.1).
In conclusion, indoximod in combination with Ad.p53-DC was safe and well-tolerated in patients with solid tumors and invasive breast cancer.
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Scientific article publishing date : 10/01/2018
Immucura identifier : BSC21_058EN