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

Abstract

BackgroundDespite 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 (αPD1) and/or Brafi, particularly those with multifocal/disseminated disease remains a major unmet clinical need.MethodsMice developing induced/spontaneous BrafV600E/Pten−/− melanomas were treated by cutaneous immunization with a DNA vaccine encoding the melanoma-associated antigen TRP2, with Brafi or αPD1 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.ResultsVaccination 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 αPD1. The therapeutic efficacy of the vaccine was associated with host skin-resident cells, the induction of a systemic, broadly reactive IFNγ+CD8+ T cell repertoire, increased frequencies of CD8+ TIL and reduced levels of PD1hi/intCD8+ T cells. Extended survival was associated with improved TIL functionality, exemplified by the presence of enhanced levels of IFNγ+CD8+ TIL and IL2+CD4+ TIL.ConclusionsThese data support the use of a novel genetic vaccine for the effective treatment of localized or multifocal melanoma refractory to conventional αPD1-based and/or Brafi-based (immune)therapy.

The Challenging Melanoma Landscape: From Early Drug Discovery to Clinical Approval

“…Moreover, BRAF/PTEN-mutated mouse models have also allowed the study of the molecular mechanisms underlying melanoma, namely the role of the Activating Molecule in Beclin-1-Regulated Autophagy in the development of this cancer [251], as well as the identification of new therapeutic targets, such as sirtuin 5 [252]. In addition, novel anticancer vaccines have also emerged as effective therapies towards melanoma as demonstrated in B6-Tyr-Cre ERT2 BRAF CA PTEN lox/lox [253] and B6.Cg-BRAF tm1Mmcm PTEN tm1Hwu Tg(Tyr-cre/ERT2)13Bos/BosJ [254] mice. Furthermore, bitransgenic [255] and hepatocyte growth factor/scatter factor (HGF/SF) transgenic [256] mice have also been used, as well as models including other relevant genes, such as the metastasis suppressor gene NME1 [257], and the oncogene GNAQ [258].…”

Analyzing Prognostic Hub Genes in the Microenvironment of Cutaneous Melanoma by Computer Integrated Bioinformatics

“…As of late, the incidence and mortality of CM are increasing. Fortunately, innovative immunotherapy strategies, including therapies using anti‐PD1, anti‐PD-L1, and anti‐CTLA4, have effectively improved patient prognosis [ 3 – 5 ]. However, only approximately 40% of patients who receive immunotherapy are able to achieve effective long-term remission [ 6 ].…”