A lot of hope for high-risk cancers is being pinned on immunotherapy but the evidence in children is lacking due to the rarity and limited efficacy of single-agent approaches. Here, we aim to assess the effectiveness of multimodal therapy comprising a personalized dendritic cell (DC) vaccine in children with relapsed and/or high-risk solid tumors using the N-of-1 approach in real-world scenario. A total of 160 evaluable events occurred in 48 patients during the 4-year follow-up. Overall survival of the cohort was 7.03 years. Disease control after vaccination was achieved in 53.8% patients. Comparative survival analysis showed the beneficial effect of DC vaccine beyond 2 years from initial diagnosis (HR = 0.53, P = .048) or in patients with disease control (HR = 0.16, P = .00053). A trend for synergistic effect with metronomic cyclophosphamide and/or vinblastine was indicated (HR = 0.60 P = .225). A strong synergistic effect was found for immune check-point inhibitors (ICIs) after priming with the DC vaccine (HR = 0.40, P = .0047). In conclusion, the personalized DC vaccine was an effective component in the multimodal individualized treatment. Personalized DC vaccine was effective in less burdened or more indolent diseases with a favorable safety profile and synergized with metronomic and/or immunomodulating agents.

Central European Advanced Therapy and Immunotherapy Centre Faculty of Medicine Masaryk University Brno Czech Republic

Department of Biology Faculty of Medicine and Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Clinical Immunology and Allergology St Anne's University Hospital in Brno Faculty of Medicine Masaryk University Brno Czech Republic

Department of Laboratory Medicine University Hospital Brno Brno Czech Republic

Department of Laboratory Methods Faculty of Medicine Masaryk University Brno Czech Republic

Department of Pathology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Pediatric Hematology and Biochemistry Children's University Hospital Brno Brno Czech Republic

Department of Pediatric Oncology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Pharmacology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Pharmacy University Hospital Brno Brno Czech Republic

International Clinical Research Centre St Anne's University Hospital in Brno Brno Czech Republic

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Gatta G, Botta L, Rossi S, et al. Childhood cancer survival in Europe 1999–2007: results of EUROCARE‐5—a population‐based study. Lancet Oncol. 2014;15(1):35‐47. doi:10.1016/S1470‐2045(13)70548‐5

Church AJ, Corson LB, Kao PC, et al. Molecular profiling identifies targeted therapy opportunities in pediatric solid cancer. Nat Med. 2022;28(8):1581‐1589. doi:10.1038/s41591‐022‐01856‐6

Geoerger B, Kang HJ, Yalon‐Oren M, et al. Pembrolizumab in paediatric patients with advanced melanoma or a PD‐L1‐positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE‐051): interim analysis of an open‐label, single‐arm, phase 1–2 trial. Lancet Oncol. 2020;21(1):121‐133. doi:10.1016/S1470‐2045(19)30671‐0

Geoerger B, Zwaan CM, Marshall LV, et al. Atezolizumab for children and young adults with previously treated solid tumours, non‐Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): a multicentre phase 1–2 study. Lancet Oncol. 2020;21(1):134‐144. doi:10.1016/S1470‐2045(19)30693‐X

Yamanaka R, Homma J, Yajima N, et al. Clinical evaluation of dendritic cell vaccination for patients with recurrent glioma: results of a clinical phase I/II trial. Clin Cancer Res. 2005;11(11):4160‐4167. doi:10.1158/1078‐0432.CCR‐05‐0120

Wang QT, Nie Y, Sun SN, et al. Tumor‐associated antigen‐based personalized dendritic cell vaccine in solid tumor patients. Cancer Immunol Immunother. 2020;69(7):1375‐1387. doi:10.1007/s00262‐020‐02496‐w

de Bruijn S, Anguille S, Verlooy J, et al. Dendritic cell‐based and other vaccination strategies for pediatric cancer. Cancer. 2019;11(9):1396. doi:10.3390/cancers11091396

Shalita C, Hanzlik E, Kaplan S, Thompson EM. Immunotherapy for the treatment of pediatric brain tumors: a narrative review. Transl Pediatr. 2022;11(12):2040‐2056. doi:10.21037/tp‐22‐86

Fehres CM, Unger WWJ, Garcia‐Vallejo JJ, Van Kooyk Y. Understanding the biology of antigen cross‐presentation for the design of vaccines against cancer. Front Immunol. 2014;5:5. doi:10.3389/fimmu.2014.00149

Calmeiro J, Carrascal MA, Tavares AR, et al. Dendritic cell vaccines for cancer immunotherapy: the role of human conventional type 1 dendritic cells. Pharmaceutics. 2020;12(2):158. doi:10.3390/pharmaceutics12020158

Neradil J, Kyr M, Polaskova K, et al. Phospho‐protein arrays as effective tools for screening possible targets for kinase inhibitors and their use in precision pediatric oncology. Front Oncol. 2019;9:930. doi:10.3389/fonc.2019.00930

Hlavackova E, Pilatova K, Cerna D, et al. 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. Front Oncol. 2019;9:1034. doi:10.3389/fonc.2019.01034

Fedorova L, Mudry P, Pilatova K, et al. Assessment of immune response following dendritic cell‐based immunotherapy in pediatric patients with relapsing sarcoma. Front Oncol. 2019;9:1169. doi:10.3389/fonc.2019.01169

Kyr M, Polaskova K, Kuttnerova Z, et al. Individualization of treatment improves the survival of children with high‐risk solid tumors: comparative patient series analysis in a real‐life scenario. Front Oncol. 2019;9:644. doi:10.3389/fonc.2019.00644

Kyr M, Svobodnik A, Stepanova R, Hejnova R. N‐of‐1 trials in pediatric oncology: from a population‐based approach to personalized medicine—a review. Cancer. 2021;13(21):5428. doi:10.3390/cancers13215428

R Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing; 2022 https://www.R-project.org/

Zhang Z, Reinikainen J, Adeleke KA, Pieterse ME, Groothuis‐Oudshoorn CGM. Time‐varying covariates and coefficients in Cox regression models. Ann Transl Med. 2018;6(7):121. doi:10.21037/atm.2018.02.12

Box‐Steffensmeier JM, De Boef S. Repeated events survival models: the conditional frailty model. Stat Med. 2006;25(20):3518‐3533. doi:10.1002/sim.2434

Prentice RL, Williams BJ, Peterson AV. On the regression analysis of multivariate failure time data. Biometrika. 1981;68(2):373‐379. doi:10.1093/biomet/68.2.373

Von Hoff DD, Stephenson JJ, Rosen P, et al. Pilot study using molecular profiling of patients' tumors to find potential targets and select treatments for their refractory cancers. JCO. 2010;28(33):4877‐4883. doi:10.1200/JCO.2009.26.5983

Simon T, Berthold F, Borkhardt A, Kremens B, De Carolis B, Hero B. Treatment and outcomes of patients with relapsed, high‐risk neuroblastoma: results of German trials: outcome of relapsed, high‐risk neuroblastoma. Pediatr Blood Cancer. 2011;56(4):578‐583. doi:10.1002/pbc.22693

Huybrechts S, Le Teuff G, Tauziède‐Espariat A, et al. Prognostic clinical and biologic features for overall survival after relapse in childhood medulloblastoma. Cancer. 2020;13(1):53. doi:10.3390/cancers13010053

Oberlin O, Rey A, Lyden E, et al. Prognostic factors in metastatic rhabdomyosarcomas: results of a pooled analysis from United States and European Cooperative Groups. JCO. 2008;26(14):2384‐2389. doi:10.1200/JCO.2007.14.7207

Barker LM, Pendergrass TW, Sanders JE, Hawkins DS. Survival after recurrence of Ewing's sarcoma family of tumors. JCO. 2005;23(19):4354‐4362. doi:10.1200/JCO.2005.05.105

Johnston DL, Keene D, Strother D, et al. Survival following tumor recurrence in children with medulloblastoma. J Pediatr Hematol Oncol. 2018;40(3):e159‐e163. doi:10.1097/MPH.0000000000001095

Ritzmann TA, Rogers HA, Paine SML, et al. A retrospective analysis of recurrent pediatric ependymoma reveals extremely poor survival and ineffectiveness of current treatments across central nervous system locations and molecular subgroups. Pediatr Blood Cancer. 2020;67(9):e28426. doi:10.1002/pbc.28426

Mackall CL, Rhee EH, Read EJ, et al. A pilot study of consolidative immunotherapy in patients with high‐risk pediatric sarcomas. Clin Cancer Res. 2008;14(15):4850‐4858. doi:10.1158/1078‐0432.CCR‐07‐4065

Gulley JL, Madan RA, Schlom J. Impact of tumour volume on the potential efficacy of therapeutic vaccines. Curr Oncol. 2011;18(3):150‐157. doi:10.3747/co.v18i3.783

Polaskova K, Merta T, Martincekova A, et al. Comprehensive molecular profiling for relapsed/refractory pediatric Burkitt lymphomas—retrospective analysis of three real‐life clinical cases—addressing issues on randomization and customization at the bedside. Front Oncol. 2020;9:1531. doi:10.3389/fonc.2019.01531

Kim SI, Cassella CR, Byrne KT. Tumor burden and immunotherapy: impact on immune infiltration and therapeutic outcomes. Front Immunol. 2021;11:629722. doi:10.3389/fimmu.2020.629722

Veltman JD, Lambers MEH, van Nimwegen M, et al. Low‐dose cyclophosphamide synergizes with dendritic cell‐based immunotherapy in antitumor activity. J Biomed Biotechnol. 2010;2010:1‐10. doi:10.1155/2010/798467

Tanaka H, Matsushima H, Nishibu A, Clausen BE, Takashima A. Dual therapeutic efficacy of vinblastine as a unique chemotherapeutic agent capable of inducing dendritic cell maturation. Cancer Res. 2009;69(17):6987‐6994. doi:10.1158/0008‐5472.CAN‐09‐1106

Kleponis J, Skelton R, Zheng L. Fueling the engine and releasing the break: combinational therapy of cancer vaccines and immune checkpoint inhibitors. Cancer Biol Med. 2015;12(3):201‐208. doi:10.7497/j.issn.2095‐3941.2015.0046

Zhao J, Chen Y, Ding ZY, Liu JY. Safety and efficacy of therapeutic cancer vaccines alone or in combination with immune checkpoint inhibitors in cancer treatment. Front Pharmacol. 2019;10:1184. doi:10.3389/fphar.2019.01184

Calmeiro J, Carrascal MA, Tavares AR, et al. Pharmacological combination of nivolumab with dendritic cell vaccines in cancer immunotherapy: an overview. Pharmacol Res. 2021;164:105309. doi:10.1016/j.phrs.2020.105309

van Willigen WW, Bloemendal M, Gerritsen WR, Schreibelt G, de Vries IJM, Bol KF. Dendritic cell cancer therapy: vaccinating the right patient at the right time. Front Immunol. 2018;9:2265. doi:10.3389/fimmu.2018.02265

Boudewijns S, Koornstra RHT, Westdorp H, et al. Ipilimumab administered to metastatic melanoma patients who progressed after dendritic cell vaccination. Onco Targets Ther. 2016;5(8):e1201625. doi:10.1080/2162402X.2016.1201625

Zapletalova D, André N, Deak L, et al. Metronomic chemotherapy with the COMBAT regimen in advanced pediatric malignancies: a multicenter experience. Oncology. 2012;82(5):249‐260. doi:10.1159/000336483

Shi W, Yang X, Xie S, et al. A new PD‐1‐specific nanobody enhances the antitumor activity of T‐cells in synergy with dendritic cell vaccine. Cancer Lett. 2021;522:184‐197. doi:10.1016/j.canlet.2021.09.028

Gao S, Wang J, Zhu Z, et al. Effective personalized neoantigen vaccine plus anti‐PD‐1 in a PD‐1 blockade‐resistant lung cancer patient. Immunotherapy. 2023;15(2):57‐69. doi:10.2217/imt‐2021‐0339

Teng C, Wang T, Shih F, Shyu W, Jeng L. Therapeutic efficacy of dendritic cell vaccine combined with programmed death 1 inhibitor for hepatocellular carcinoma. J Gastroenterol Hepatol. 2021;36(7):1988‐1996. doi:10.1111/jgh.15398

Cornelissen R, Hegmans JPJJ, Maat APWM, et al. Extended tumor control after dendritic cell vaccination with low‐dose cyclophosphamide as adjuvant treatment in patients with malignant pleural mesothelioma. Am J Respir Crit Care Med. 2016;193(9):1023‐1031. doi:10.1164/rccm.201508‐1573OC

Olsen HE, Lynn GM, Valdes PA, et al. Therapeutic cancer vaccines for pediatric malignancies: advances, challenges, and emerging technologies. Neuro‐oncol Adv. 2021;3(1):vdab027. doi:10.1093/noajnl/vdab027

Raj S, Bui MM, Springett G, et al. Long‐term clinical responses of neoadjuvant dendritic cell infusions and radiation in soft tissue sarcoma. Sarcoma. 2015;2015:1‐8. doi:10.1155/2015/614736

Merchant MS, Bernstein D, Amoako M, et al. Adjuvant immunotherapy to improve outcome in high‐risk pediatric sarcomas. Clin Cancer Res. 2016;22(13):3182‐3191. doi:10.1158/1078‐0432.CCR‐15‐2550

Krishnadas DK, Shusterman S, Bai F, et al. A phase I trial combining decitabine/dendritic cell vaccine targeting MAGE‐A1, MAGE‐A3 and NY‐ESO‐1 for children with relapsed or therapy‐refractory neuroblastoma and sarcoma. Cancer Immunol Immunother. 2015;64(10):1251‐1260. doi:10.1007/s00262‐015‐1731‐3

Medikonda R, Dunn G, Rahman M, Fecci P, Lim M. A review of glioblastoma immunotherapy. J Neurooncol. 2021;151(1):41‐53. doi:10.1007/s11060‐020‐03448‐1

Di Maio M, Perrone F, Conte P. Real‐world evidence in oncology: opportunities and limitations. Oncologist. 2020;25(5):e746‐e752. doi:10.1634/theoncologist.2019‐0647

Individualized therapeutic approaches for relapsed and refractory pediatric ependymomas: a single institution experience