Dendritic Cell-Based Immunotherapy in Advanced Sarcoma and Neuroblastoma Pediatric Patients: ...

@article{1591356,
   author = {Hlaváčková, Eva and Pilátová, Kateřina and Černá, Dáša and Selingerova, Iveta and Múdry, Peter and Mazánek, Pavel and Fědorová, Lenka and Merhautová, Jana and Jurečková, Lucie and Semerád, Lukáš and Pacasova, Rita and Flajšarová, Lucie and Součková, Lenka and Demlová, Regina and Štěrba, Jaroslav and Valík, Dalibor and Zdražilová Dubská, Lenka},
   article_location = {Lausanne},
   article_number = {OCT 25 2019},
   doi = {http://dx.doi.org/10.3389/fonc.2019.01034},
   keywords = {dendritic cells; anti-cancer medications; sarcoma; neuroblastoma; cell-based medicinal products; investigator-initiated clinical trial; manufacturing outcome variability},
   language = {eng},
   issn = {2234-943X},
   journal = {Frontiers in Oncology},
   title = {Dendritic Cell-Based Immunotherapy in Advanced Sarcoma and Neuroblastoma Pediatric Patients: Anti-cancer Treatment Preceding Monocyte Harvest Impairs the Immunostimulatory and Antigen-Presenting Behavior of DCs and Manufacturing Process Outcome},
   url = {http://dx.doi.org/10.3389/fonc.2019.01034},
   volume = {9},
   year = {2019}
}

TY  - JOUR
ID  - 1591356
AU  - Hlaváčková, Eva - Pilátová, Kateřina - Černá, Dáša - Selingerova, Iveta - Múdry, Peter - Mazánek, Pavel - Fědorová, Lenka - Merhautová, Jana - Jurečková, Lucie - Semerád, Lukáš - Pacasova, Rita - Flajšarová, Lucie - Součková, Lenka - Demlová, Regina - Štěrba, Jaroslav - Valík, Dalibor - Zdražilová Dubská, Lenka
PY  - 2019
TI  - Dendritic Cell-Based Immunotherapy in Advanced Sarcoma and Neuroblastoma Pediatric Patients: Anti-cancer Treatment Preceding Monocyte Harvest Impairs the Immunostimulatory and Antigen-Presenting Behavior of DCs and Manufacturing Process Outcome
JF  - Frontiers in Oncology
VL  - 9
IS  - OCT 25 2019
SP  - 1-15
EP  - 1-15
PB  - Frontiers Media S.A.
SN  - 2234943X
KW  - dendritic cells
KW  - anti-cancer medications
KW  - sarcoma
KW  - neuroblastoma
KW  - cell-based medicinal products
KW  - investigator-initiated clinical trial
KW  - manufacturing outcome variability
UR  - http://dx.doi.org/10.3389/fonc.2019.01034
L2  - http://dx.doi.org/10.3389/fonc.2019.01034
N2  - 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.
ER  - 

HLAVÁČKOVÁ, Eva, Kateřina PILÁTOVÁ, Dáša ČERNÁ, Iveta SELINGEROVA, Peter MÚDRY, Pavel MAZÁNEK, Lenka FĚDOROVÁ, Jana MERHAUTOVÁ, Lucie JUREČKOVÁ, Lukáš SEMERÁD, Rita PACASOVA, Lucie FLAJŠAROVÁ, Lenka SOUČKOVÁ, Regina DEMLOVÁ, Jaroslav ŠTĚRBA, Dalibor VALÍK a Lenka ZDRAŽILOVÁ DUBSKÁ. Dendritic Cell-Based Immunotherapy in Advanced Sarcoma and Neuroblastoma Pediatric Patients: Anti-cancer Treatment Preceding Monocyte Harvest Impairs the Immunostimulatory and Antigen-Presenting Behavior of DCs and Manufacturing Process Outcome. \textit{Frontiers in Oncology}. Lausanne: Frontiers Media S.A., roč.~9, OCT 25 2019, s.~1-15. ISSN~2234-943X. doi:10.3389/fonc.2019.01034. 2019.