Skin immunization for effective treatment of multifocal melanoma refractory to PD1 blockade and Braf inhibitors

Background Despite the remarkable benefits associated with the interventional treatment of melanomas (and other solid cancers) with immune checkpoint and Braf inhibitors (Brafi), most patients ultimately progress on therapy. The presence of multifocal/disseminated disease in patients increases their mortality risk. Hence, the development of novel strategies to effectively treat patients with melanomas that are resistant to anti-PD1 mAb (alpha PD1) and/or Brafi, particularly those with multifocal/disseminated disease remains a major unmet clinical need. Methods Mice developing induced/spontaneous Braf(V600E)/Pten(-/-) melanomas were treated by cutaneous immunization with a DNA vaccine encoding the melanoma-associated antigen TRP2, with Brafi or alpha PD1 alone, or with a combination of these treatments. Tumor progression, tumor-infiltration by CD4(+) and CD8(+) T cells, and the development of TRP2-specific CD8(+) T cells were then monitored over time. Results Vaccination led to durable antitumor immunity against PD1/Brafi-resistant melanomas in both single lesion and multifocal disease models, and it sensitized PD1-resistant melanomas to salvage therapy with alpha PD1. The therapeutic efficacy of the vaccine was associated with host skin-resident cells, the induction of a systemic, broadly reactive IFN gamma(+)CD8(+) T cell repertoire, increased frequencies of CD8(+) TIL and reduced levels of PD1(hi/int)CD8(+) T cells. Extended survival was associated with improved TIL functionality, exemplified by the presence of enhanced levels of IFN gamma(+)CD8(+) TIL and IL2(+)CD4(+) TIL. Conclusions These data support the use of a novel genetic vaccine for the effective treatment of localized or multifocal melanoma refractory to conventional alpha PD1-based and/or Brafi-based (immune)therapy.

Automated summary

The development of novel strategies to effectively treat patients with melanomas that are resistant to anti-PD1 mAb and/or Brafi, particularly those with multifocal/disseminated disease, is an unmet clinical need. In a study on mice with induced/spontaneous Braf(V600E)/Pten(-/-) melanomas, vaccination with a DNA vaccine encoding TRP2 led to durable antitumor immunity and sensitized PD1-resistant melanomas to salvage therapy with alpha PD1. The therapeutic efficacy of the vaccine was associated with the induction of a systemic, broadly reactive IFN gamma(+)CD8(+) T cell repertoire, increased frequencies of CD8(+) TIL, and reduced levels of PD1(hi/int)CD8(+) T cells.