Abstract
Despite efforts to develop novel treatment strategies, refractory and relapsing sarcoma, and high-risk neuroblastoma continue to have poor prognoses and limited overall survival. Monocyte-derived dendritic cell (DC)-based anti-cancer immunotherapy represents a promising treatment modality in these neoplasias. A DC-based anti-cancer vaccine was evaluated for safety in an academic phase-I/II clinical trial for children, adolescents, and young adults with progressive, recurrent, or primarily metastatic high-risk tumors, mainly sarcomas and neuroblastomas. The DC vaccine was loaded with self-tumor antigens obtained from patient tumor tissue. DC vaccine quality was assessed in terms of DC yield, viability, immunophenotype, production of IL-12 and IL-10, and stimulation of allogenic donor T-cells and autologous T-cells in allo-MLR and auto-MLR, respectively. Here, we show that the outcome of the manufacture of DC-based vaccine is highly variable in terms of both DC yield and DC immunostimulatory properties. In 30% of cases, manufacturing resulted in a product that failed to meet medicinal product specifications and therefore was not released for administration to a patient. Focusing on the isolation of monocytes and the pharmacotherapy preceding monocyte harvest, we show that isolation of monocytes by elutriation is not superior to adherence on plastic in terms of DC yield, viability, or immunostimulatory capacity. Trial patients having undergone monocyte-interfering pharmacotherapy prior to monocyte harvest was associated with an impaired DC-based immunotherapy product outcome. Certain combinations of anti-cancer treatment resulted in a similar pattern of inadequate DC parameters, namely, a combination of temozolomide with irinotecan was associated with DCs showing poor maturation and decreased immunostimulatory features, and a combination of pazopanib, topotecan, and MTD-based cyclophosphamide was associated with poor monocyte differentiation and decreased DC immunostimulatory parameters. Searching for a surrogate marker predicting an adverse outcome of DC manufacture in the peripheral blood complete blood count prior to monocyte harvest, we observed an association between an increased number of immature granulocytes in peripheral blood and decreased potency of the DC-based product as quantified by allo-MLR. We conclude that the DC-manufacturing yield and the immunostimulatory quality of anti-cancer DC-based vaccines generated from the monocytes of patients were not influenced by the monocyte isolation modality but were detrimentally affected by the specific combination of anti-cancer agents used prior to monocyte harvest.
Highlights
Several progressive and relapsing malignancies in pediatric patients have dismal life prognosis
We show that despite strict adherence to the validated manufacturing protocol, the outcome of the manufacture of the medicinal product with monocyte-derived DCs is highly variable in terms of both DC yield and immunostimulatory properties
In 30% of cases, manufacture of DCbased immunotherapy for advanced sarcoma and high-risk neuroblastoma patients resulted in a product that did not meet the specifications for the medicinal product and was not released for application
Summary
Several progressive and relapsing malignancies in pediatric patients have dismal life prognosis. The cytotoxic chemotherapy regimens for relapsed and refractory neuroblastoma typically use a combination of camptothecins, topotecan, and irinotecan with agents such as cyclophosphamide and temozolomide, and achieve objective tumor responses but poor long-term outcomes. For such poor-prognosis patients, treatments with innovative and metronomic therapies (e.g., COMBAT, METRO) [4, 5], cell-based immunotherapies [6, 7], and novel molecularly targeted agents [8] are justified and are effective in many cases, their long-term effect has yet to be demonstrated
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