Skin immunization for effective treatment of multifocal melanoma refractory to PD1 blockade and Braf inhibitors
Open Access
- 6 January 2021
- journal article
- research article
- Published by BMJ in Journal for ImmunoTherapy of Cancer
- Vol. 9 (1), e001179
- https://doi.org/10.1136/jitc-2020-001179
Abstract
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 (αPD1) and/or Brafi, particularly those with multifocal/disseminated disease remains a major unmet clinical need. Methods Mice 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. 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 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. Conclusions These 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.Funding Information
- NIH (P50 CA121973; R01 CA204419; R21 CA191522)
This publication has 83 references indexed in Scilit:
- Host immunity contributes to the anti-melanoma activity of BRAF inhibitorsJCI Insight, 2013
- Selective BRAF Inhibitors Induce Marked T-cell Infiltration into Human Metastatic MelanomaClinical Cancer Research, 2012
- Genetic Targeting of the Active Transcription Factor XBP1s to Dendritic Cells Potentiates Vaccine-induced Prophylactic and Therapeutic Antitumor ImmunityMolecular Therapy, 2012
- Resistance to BRAF Inhibitors: Unraveling Mechanisms and Future Treatment OptionsCancer Research, 2011
- Systems biology of vaccination for seasonal influenza in humansNature Immunology, 2011
- ER stress and its regulator X‐box‐binding protein‐1 enhance polyIC‐induced innate immune response in dendritic cellsEuropean Journal of Immunology, 2011
- Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanomaNature, 2010
- TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophagesNature Immunology, 2010
- BrafV600E cooperates with Pten loss to induce metastatic melanomaNature Genetics, 2009
- The transcription factor XBP-1 is essential for the development and survival of dendritic cellsThe Journal of Experimental Medicine, 2007