Autologous monocyte-derived DC vaccination combined with cisplatin in stage III and IV melanoma patients: a prospective, randomized phase 2 trial

Abstract

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.

mRNA therapeutics in cancer immunotherapy

“…and i.v.) Melanoma NCT02285413 (II, randomized) Cisplatin 2011 Completed [ 35 ] University Hospital Erlangen Tumor mRNA Uveal melanoma NCT01983748 (III, randomized) None 2014 Recruiting University of Campinas WT1 mRNA Myelodysplastic syndromes, AML NCT03083054 (I/II) None 2016 Active, not recruiting University of Florida Total tumor mRNA and ex vivo expanded lymphocytes (i.v. and i.d.)…”

Combining chemotherapy and autologous peptide‐pulsed dendritic cells provides survival benefit in stage IV melanoma patients

“…Therefore, we recommend that only patients with specific, well-defined HLA haplotype characteristics should be enrolled in future vaccination trials using peptide-loaded DCs. There is increasing evidence for a potential synergistic effect of DC vaccination and conventional chemotherapy [29][30][31][32]. The development of drug resistance to conventional chemotherapy is considered to be the major cause for treatment failure in many types of cancer.…”

“…There is increasing evidence for a potential synergistic effect of DC vaccination and conventional chemotherapy [29–32]. The development of drug resistance to conventional chemotherapy is considered to be the major cause for treatment failure in many types of cancer.…”

Kombination von Chemotherapie und autologen, Peptid‐beladenen dendritischen Zellen bringt Überlebensvorteil bei Melanompatienten im Stadium IV

“…Die Evidenz für potenzielle synergistische Wirkungen von DZ‐Vakzination und konventioneller Chemotherapie nimmt zu [29–32]. Die Entwicklung von Resistenzen gegen konventionelle Chemotherapie wird als Hauptursache für Therapieversagen in vielen Arten von Krebs betrachtet.…”