Adjuvant Dendritic Cells Vaccine combined with Cytokine-Induced Killer cell Therapy after Renal Cell Carcinoma surgery

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Summary

This study observes the side effects and efficacy of Dendritic Cells’ (DCs) vaccine in combination with cytokine-induced killer cell (CIK) therapy after renal cell carcinoma (RCC) surgery (RCCS). The results reveal, RCCS DCs-CIK treatment prolonged PFS and reduced mortality, showing better overall activity.

Patients characteristics

410 patients age >18 years old with WHO-ECOG performance status 0-1; patients with radical or partial nephrectomy, and pathologically diagnosed renal cell carcinoma (RCC); expected survival more than 3 months. With adequate bone marrow, renal function and liver function.

Methodology

50 ml of peripheral anticoagulated whole blood were collected from each patient before surgery and every 10 days before treatment. The density gradient centrifugation method and human lymphocyte separation medium were used to separate the mononuclear cells; then the lymphocyte serum-free medium (AMMS) was added for 3-hour culture. The suspended cells and adherent cells were then collected for future use.
The wall-adherent DCs were then cultured with lymphocyte serum-free medium, and the cytokines were then added with the following final concentrations: granulocyte-macrophage colony- stimulating factor (GM-CSF), IL-4 and tumor necrosis factor-α (TNF-α); half of the amount of medium was changed every 3 days, and an equal amount of fresh cytokines was complemented. On the 7th day of culture, the prepared tumor antigens were added into the DC culture system at a final concentration of 20 μg/ml, and then the mixture was cultured at 37°C for 2-3 days after which the autologous tumor antigen loaded DCs were obtained.
Culture of CIK cells
The suspended cells were collected and adjusted with the serum-free medium to a cell concentration of 4×106 cells/ml; then the cell suspension was cultured at 37°C and 5% CO2 for 2 hrs. The non-wall-adherent cells were collected, and the concentration was adjusted with the serum-free medium to 2×106 cells/ml. Following this, interferon-γ (IFN-γ) were added and cultured at 37°C and 5% CO2 for 24 hours; on the next day, 1 μg/ml mouse anti-human CD3 monoclonal antibody and IL-2 were added and kept into the culture. Half of the amount of the medium was changed every 3 days, and an equal amount of IL-2 was complemented.

Treatment

The study group began the DC-CIK bio-immunotherapy 2-3 weeks postoperatively. DCs vaccine therapy: 1 ml of intradermally injected preparation in the inguinal regions bilaterally (the lymphatic drainage area), with a cell number of 2-5×106/ per day, for a total of 6 courses.
CIK therapy administered on the second of DCs vaccine treatment consisted of IV infusion of 3- 6×109 cells (100 ml) in one hour/once a day for a total of 5 courses. A 6-day treatment wasconsidered as one course, and the second course started after one month interval, for a total of 3 courses.The control group received conventional IFN-α therapy postoperatively, with 3×106 units, 3 times/ week, for a total of 3 months.

Results

Disease progression situations
The follow up period of this research ranged from 13 to 57 months (median 35). In the study group (DCs-CIK group) we noticed 1 case of local recurrence, 1 case of metastasis and 5 deaths. At the same time no case of local recurrence, 5 cases of metastasis and 34 deaths were registered in the control group (INF-α group).
Clinical outcome
During follow-up, 5 of 154 (3.2%) patients of the DCs-CIK group died, and the mean 3-and 5-year OS rates were both 96 ± 2%.
In the IFN-α group 34 (13.3%) patients died, with a mean 3-year and 5-year OS rate 83 ± 3% and 74 ± 6%, respectively. The difference of OS between the two groups was statistically significant indicating that DCs- CIK treatment could significantly improve the 3- and 5-year OS rates of RCC patients compared INF-a therapy.
Adverse reactions
The main side effects of IFN-α therapy were flu-like symptoms (fever, fatigue and muscle pain), often occurring within the first 2 weeks of treatment. During treatment, 31% of the cases exhibited leukopenia, necessitating administration of G-CSF; 14% of the cases exhibited liver toxicity (mostly grade I-II); 7% of the cases developed proteinuria and 23 (9.0%) patients were withdrawn from treatment because of fever and liver dysfunction.
The patients in the DCs-CIK group exhibited good tolerance, without serious adverse events. The main adverse reaction was transient low-grade fever (below 38oC), which usually occurred within 2-6 hours post infusion, and was accompanied with fatigue; this side effect usually lasted 3-5 hours, and subsided spontaneously. No severe toxicity such as leukopenia, hypotension, allergy, pulmonary edema, liver and kidney dysfunction were observed, and no patient was withdrawn be- cause of adverse effects.

Conclusion

Adjuvant post-RCCS DCs-CIK treatment prolonged PFS and reduced mortality, showing better over- all activity compared to interferon treatment.

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Scientific article publishing date 11/11/2014

Immucura identifier BSC21_238EN

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