Immunogenicity in humans of a transdermal multipeptide melanoma vaccine administered with or without a TLR7 agonist
Background Experimental 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 ma...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2021-05-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/9/5/e002214.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832542551843799040 |
|---|---|
| author | Craig L Slingluff Gina R Petroni Walter C Olson Kimberly A Chianese-bullock Donna Deacon Mark Smolkin William W Grosh Max O Meneveau Kevin T Lynch Elise P Salerno Elizabeth Woodson James W Patterson |
| author_facet | Craig L Slingluff Gina R Petroni Walter C Olson Kimberly A Chianese-bullock Donna Deacon Mark Smolkin William W Grosh Max O Meneveau Kevin T Lynch Elise P Salerno Elizabeth Woodson James W Patterson |
| author_sort | Craig L Slingluff |
| collection | DOAJ |
| description | Background Experimental 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.Methods Twelve 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.Results CD8+ 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%.Conclusions These 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. |
| format | Article |
| id | doaj-art-f51a03367fd14cc38bf39a029258d603 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2021-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-f51a03367fd14cc38bf39a029258d6032025-02-04T03:10:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-05-019510.1136/jitc-2020-002214Immunogenicity in humans of a transdermal multipeptide melanoma vaccine administered with or without a TLR7 agonistCraig L Slingluff0Gina R Petroni1Walter C Olson2Kimberly A Chianese-bullock3Donna Deacon4Mark Smolkin5William W Grosh6Max O Meneveau7Kevin T Lynch8Elise P Salerno9Elizabeth Woodson10James W Patterson111University of Virginia, Charlottesville, VA, USA2University of Virginia, Charlottesville, VA, USA1 Department of Surgery, University of Virginia Health System, Charlottesville, Virginia, USA2University of Virginia, Charlottesville, VA, USASurgery, University of Virginia School of Medicine, Charlottesville, Virginia, USAPublic Health Sciences, University of Virginia School of Medicine, Charlottesville, Virginia, USA4 Department of Medicine, Division of Hematology/Oncology University of Virginia, Charlottesville, Virginia, USA1 Department of Surgery, University of Virginia Health, Charlottesville, Virginia, USA1 Department of Surgery, University of Virginia Health, Charlottesville, Virginia, USASurgery, University of Virginia School of Medicine, Charlottesville, Virginia, USACancer Center, University of Virginia Health System, Charlottesville, Virginia, USAPathology, University of Virginia, Charlottesville, Virginia, USABackground Experimental 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.Methods Twelve 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.Results CD8+ 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%.Conclusions These 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.https://jitc.bmj.com/content/9/5/e002214.full |
| spellingShingle | Craig L Slingluff Gina R Petroni Walter C Olson Kimberly A Chianese-bullock Donna Deacon Mark Smolkin William W Grosh Max O Meneveau Kevin T Lynch Elise P Salerno Elizabeth Woodson James W Patterson Immunogenicity in humans of a transdermal multipeptide melanoma vaccine administered with or without a TLR7 agonist Journal for ImmunoTherapy of Cancer |
| title | Immunogenicity in humans of a transdermal multipeptide melanoma vaccine administered with or without a TLR7 agonist |
| title_full | Immunogenicity in humans of a transdermal multipeptide melanoma vaccine administered with or without a TLR7 agonist |
| title_fullStr | Immunogenicity in humans of a transdermal multipeptide melanoma vaccine administered with or without a TLR7 agonist |
| title_full_unstemmed | Immunogenicity in humans of a transdermal multipeptide melanoma vaccine administered with or without a TLR7 agonist |
| title_short | Immunogenicity in humans of a transdermal multipeptide melanoma vaccine administered with or without a TLR7 agonist |
| title_sort | immunogenicity in humans of a transdermal multipeptide melanoma vaccine administered with or without a tlr7 agonist |
| url | https://jitc.bmj.com/content/9/5/e002214.full |
| work_keys_str_mv | AT craiglslingluff immunogenicityinhumansofatransdermalmultipeptidemelanomavaccineadministeredwithorwithoutatlr7agonist AT ginarpetroni immunogenicityinhumansofatransdermalmultipeptidemelanomavaccineadministeredwithorwithoutatlr7agonist AT waltercolson immunogenicityinhumansofatransdermalmultipeptidemelanomavaccineadministeredwithorwithoutatlr7agonist AT kimberlyachianesebullock immunogenicityinhumansofatransdermalmultipeptidemelanomavaccineadministeredwithorwithoutatlr7agonist AT donnadeacon immunogenicityinhumansofatransdermalmultipeptidemelanomavaccineadministeredwithorwithoutatlr7agonist AT marksmolkin immunogenicityinhumansofatransdermalmultipeptidemelanomavaccineadministeredwithorwithoutatlr7agonist AT williamwgrosh immunogenicityinhumansofatransdermalmultipeptidemelanomavaccineadministeredwithorwithoutatlr7agonist AT maxomeneveau immunogenicityinhumansofatransdermalmultipeptidemelanomavaccineadministeredwithorwithoutatlr7agonist AT kevintlynch immunogenicityinhumansofatransdermalmultipeptidemelanomavaccineadministeredwithorwithoutatlr7agonist AT elisepsalerno immunogenicityinhumansofatransdermalmultipeptidemelanomavaccineadministeredwithorwithoutatlr7agonist AT elizabethwoodson immunogenicityinhumansofatransdermalmultipeptidemelanomavaccineadministeredwithorwithoutatlr7agonist AT jameswpatterson immunogenicityinhumansofatransdermalmultipeptidemelanomavaccineadministeredwithorwithoutatlr7agonist |