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

Area of Science:

• Oncology
• Immunotherapy
• Vaccinology

Background:

• Most patients with melanoma and other solid cancers eventually progress on therapy with immune checkpoint inhibitors (ICIs) like anti-PD1 mAb (αPD1) and BRAF inhibitors (Brafi).
• Multifocal or disseminated disease significantly increases mortality risk in these patients.
• Developing effective treatments for melanomas resistant to αPD1 and/or Brafi, especially those with widespread disease, is a critical unmet need.

Purpose of the Study:

• To evaluate the efficacy of a novel DNA vaccine encoding the melanoma-associated antigen TRP2 in preclinical models of melanoma.
• To assess the vaccine's ability to overcome resistance to αPD1 and Brafi therapies.
• To investigate the immunological mechanisms underlying the vaccine's therapeutic effects.

Main Methods:

• Mice with induced/spontaneous Braf^V600E/Pten^-/- melanomas were treated with a TRP2 DNA vaccine, Brafi, αPD1, or combinations thereof.
• Tumor progression, T cell infiltration (CD4⁺ and CD8⁺), and the development of TRP2-specific CD8⁺ T cells were monitored.

Main Results:

• The TRP2 DNA vaccine induced durable antitumor immunity in both single-lesion and multifocal melanoma models, including those resistant to αPD1 and Brafi.
• Vaccination sensitized αPD1-resistant melanomas to subsequent αPD1 treatment.
• Therapeutic efficacy correlated with increased CD8⁺ tumor-infiltrating lymphocytes (TILs), a systemic IFNγ⁺CD8⁺ T cell response, and improved TIL functionality (IFNγ⁺CD8⁺ and IL2⁺CD4⁺).

Conclusions:

• A novel genetic vaccine demonstrates significant potential for treating localized or multifocal melanoma.
• This vaccine approach is effective in preclinical models of melanoma refractory to conventional αPD1 and/or Brafi therapies.
• The findings support the clinical investigation of this DNA vaccine as a new therapeutic strategy for resistant melanoma.