Author:
Geukes Foppen Marnix H.,Rohaan Maartje W.,Borgers Jessica S.W.,Philips Daisy,Vyth-Dreese Florry,Beijnen Jos H.,Nuijen Bastiaan,van den Berg Joost H.,Haanen John B.A.G.
Abstract
<b><i>Introduction:</i></b> Naked DNA vaccination could be a powerful and safe strategy to mount antigen-specific cellular immunity. We designed a phase I clinical trial to investigate the toxicity of naked DNA vaccines encoding CD8<sup>+</sup> T-cell epitope from tumor-associated antigen MART-1 in patients with advanced melanoma. <b><i>Methods:</i></b> This dose escalating phase Ia clinical trial investigates the toxicity and immunological response upon naked DNA vaccines encoding a CD8<sup>+</sup> T-cell epitope from the tumor-associated antigen MART-1, genetically linked to the gene encoding domain 1 of subunit-tetanus toxin fragment C in patients with advanced melanoma (inoperable stage IIIC-IV, AJCC 7th edition). The vaccine was administrated via intradermal application using a permanent make-up or tattoo device. Safety was monitored according to CTCAE v.3.0 and skin biopsies and blood samples were obtained for immunologic monitoring. <b><i>Results:</i></b> Nine pretreated, HLA-A*0201-positive patients with advanced melanoma expressing MART-1 and MHC class I, with a good performance status, and adequate organ function, were included. With a median follow-up of 5.9 months, DNA vaccination was safe, without treatment-related deaths. Common treatment-emergent adverse events of any grade were dermatologic reactions at the vaccination site (100%) and pain (56%). One patient experienced grade 4 toxicity, most likely related to tumor progression. One patient (11%) achieved stable disease, lasting 353 days. Immune analysis showed no increase in vaccine-induced T cell response in peripheral blood of 5 patients, but did show a MART-1 specific CD8<sup>+</sup> T cell response at the tattoo administration site. The maximum dose administered was 2 mg due to lack of clinical activity. <b><i>Conclusion:</i></b> We showed that the developed DNA vaccine, applied using a novel intradermal application strategy, can be administered safely. Further research with improved vaccine formats is required to show possible clinical benefit of DNA vaccination.