Purpose: Thus far, dendritic cell (DC)-based immunotherapy of cancer was primarily based on in vitro-generated monocytederived DCs, which require extensive in vitro manipulation. Here, we report on a clinical study exploiting primary CD1c þ myeloid DCs, naturally circulating in the blood. Experimental Design: Fourteen stage IV melanoma patients, without previous systemic treatment for metastatic disease, received autologous CD1c þ myeloid DCs, activated by only brief (16 hours) ex vivo culture and loaded with tumor-associated antigens of tyrosinase and gp100. Results: Our results show that therapeutic vaccination against melanoma with small amounts (3-10 Â 10 6 ) of myeloid DCs is feasible and without substantial toxicity. Four of 14 patients showed long-term progression-free survival (12-35 months), which directly correlated with the development of multifunctional CD8þ T-cell responses in three of these patients. In particular, high CD107a expression, indicative for cytolytic activity, and IFNg as well as TNFa and CCL4 production was observed. Apparently, these T-cell responses are essential to induce tumor regression and promote long-term survival by stalling tumor growth. Conclusions:We show that vaccination of metastatic melanoma patients with primary myeloid DCs is feasible and safe and results in induction of effective antitumor immune responses that coincide with improved progression-free survival. Clin Cancer Res; 22(9); 2155-66. Ó2015 AACR.

No abstract

Posaconazole (PSZ) may be an attractive alternative for antifungal prophylaxis in children with chronic granulomatous disease. Experience with PSZ in pediatric patients is limited, and no specific dose recommendations exist. A twice daily dosing algorithm based on allometric scaling (body-weight based) for PSZ results in adequate exposure and appears to be safe in children with chronic granulomatous disease.

Background Autologous dendritic cell (DC) vaccines can induce tumor-specific T cells, but their effect can be counteracted by immunosuppressive mechanisms. Cisplatin has shown immunomodulatory effects in vivo which may enhance efficacy of DC vaccination. Methods This is a prospective, randomized, open-label phase 2 study (NCT02285413) including stage III and IV melanoma patients receiving 3 biweekly vaccinations of gp100 and tyrosinase mRNA-loaded monocyte-derived DCs with or without cisplatin. Primary objectives were to study immunogenicity and feasibility, and secondary objectives were to assess toxicity and survival. Results Twenty-two stage III and 32 stage IV melanoma patients were analyzed. Antigen-specific CD8 + T cells were found in 44% versus 67% and functional T cell responses in 28% versus 19% of skin-test infiltrating lymphocytes in patients receiving DC vaccination with and without cisplatin, respectively. Four patients stopped cisplatin because of toxicity and continued DC monotherapy. No therapy-related grade 3 or 4 adverse events occurred due to DC monotherapy. During combination therapy, one therapy-related grade 3 adverse event, decompensated heart failure due to fluid overload, occurred. The clinical outcome parameters did not clearly suggest significant differences. Conclusions Combination of DC vaccination and cisplatin in melanoma patients is feasible and safe, but does not seem to result in more tumor-specific T cell responses or improved clinical outcome, when compared to DC vaccination monotherapy. Keywords Dendritic cell • Vaccination • Cisplatin • Melanoma • Immunotherapy Abbreviations AJCC American Joint Cancer on Committee CBA Cytometric bead array CTCAE Common terminology criteria for adverse events DTH Delayed-type hypersensitivity EBV Epstein-Barr virus FFPE Formalin-fixed paraffin embedded HS Human serum ICI Immune checkpoint inhibitors KLH Keyhole limpet hemocyanin M-MDSC(s) Monocytic myeloid-derived suppressor cell(s) mIHC Multiplex immunohistochemistry PD-L2 Programmed death ligand 2 Steve Boudewijns, Martine Bloemendal and Nienke de Haas have contributed equally. Note on previous publication: Parts of this publication were published before in the doctoral thesis 'Dendritic cell vaccination in the evolving therapeutic landscape of melanoma' by S. Boudewijns in 2017 and in the doctoral thesis 'Novel strategies in dendritic-cell based immunotherapy-Focusing on adjuvant treatment of stage III melanoma' by M. Bloemendal in 2019 [1, 2]. Both were written at the departments of Tumor Immunology and Medical Oncology of the Radboud university medical center, Nijmegen, the Netherlands.

No abstract