Immunogenicity in humans of a transdermal multipeptide melanoma vaccine administered with or without a TLR7 agonist

Abstract

BackgroundExperimental cancer vaccines are traditionally administered by injection in subcutaneous tissue or muscle, commonly with adjuvants that create chronic inflammatory depots. Injection of melanoma-derived peptides induces T cell responses; however, the depots that form following injection may inhibit optimization of the immune response. In skin, epidermal Langerhans cells (LC) are a dominant source of professional antigen presenting cells. We hypothesized that: (1) applying melanoma-derived peptides topically, in proximity to LC, could be immunogenic and safe, with low vaccine-site toxicity and (2) topical toll-like receptor 7 (TLR7) agonist would increase immunogenicity of the peptide vaccine.MethodsTwelve melanoma peptides plus a tetanus helper peptide were combined with granulocyte macrophage colony stimulating factor (GM-CSF) and were administered topically on days 1, 8, and 15, to 28 patients randomized to one of four adjuvant preparations: (1) incomplete Freund’s adjuvant (IFA); (2) IFA plus a TLR7 agonist (imiquimod) administered on days 0, 7, 14; (3) dimethyl sulfoxide (DMSO) or (4) DMSO+ imiquimod administered on day 0, 7, 14. Every 3 weeks thereafter (x 6), the peptides were combined with GM-CSF and were injected into the dermis and subcutis in an emulsion with IFA. Toxicities were recorded and immune responses assayed by ELIspot.ResultsCD8+ T cell responses to transdermal vaccination in DMSO occurred in 83% of participants in group 3 and 86% in group 4, and responses to vaccination in IFA were observed in 29% of participants in group 1 and 14% in group 2. Overall, 61% of participants had CD4+ T cell immune responses to the tetanus peptide, with large, durable responses in groups 3 and 4. Five of seven participants in group 4 had a severe rash, one that was dose limiting. Ten-year overall survival was 67% and disease-free survival was 44%.ConclusionsThese data provide proof of principle for immunogenicity in humans of transdermal immunization using peptides in DMSO. Further study is warranted into the pharmacokinetics and immunobiology of TLR agonists as vaccine adjuvants during transcutaneous application. Overall survival is high, supporting further investigation of this immunization approach.

Improvement of Imiquimod Solubilization and Skin Retention via TPGS Micelles: Exploiting the Co-Solubilizing Effect of Oleic Acid

“…The data on malignant melanocytic proliferations, although preliminary, highlighted that, even if surgical excision remains the preferred approach, the use of imiquimod can represent a valid alternative in specific cases such as the management of persistently positive melanoma margins and the treatment of large and less defined lesions on the head and neck, most of the time requiring a disfiguring surgical intervention. Finally, imiquimod topical use as adjuvant for cancer vaccines is presently under investigation and, at the moment, it shows good tolerability and a systemic immune response [ 13 , 14 ].…”

Polymorphisms in toll-like receptor 3 and 4 genes as prognostic and outcome biomarkers in melanoma patients

“…However, due to insufficient immune activation, patients show variable response rates to immunotherapy. In the focus of immunogenic attributes of melanoma progression lie TLR signaling [17,[19][20][21]. The actual mechanisms of TLR signaling in cancer remain elusive, and only a limited number of previous studies investigated the association of TLR3 and TLR4 gene polymorphisms with melanoma progression and survival [7,14,15].…”

Peptide Vaccines in Melanoma: Chemical Approaches towards Improved Immunotherapeutic Efficacy

“…For this, DMSO and Montanide TM ISA-51 alone or in combination with TLR 7 agonist imiquimod were used. It was found that CD8 + T cell responses were stronger in DMSO-containing groups alone or in combination with imiquimod (83% and 86% of participants, respectively), compared to Montanide TM ISA-51 involved groups alone or in combination with imiquimod (28% and 14% of participants, respectively) [ 135 ].…”