TY - JOUR
T1 - Phase I/II trial of a long peptide vaccine (LPV7) plus toll-like receptor (TLR) agonists with or without incomplete Freund's adjuvant (IFA) for resected high-risk melanoma
AU - Patel, Sapna P.
AU - Petroni, Gina R.
AU - Roszik, Jason
AU - Olson, Walter C.
AU - Wages, Nolan A.
AU - Chianese-Bullock, Kimberly A.
AU - Smolkin, Mark
AU - Varhegyi, Nikole
AU - Gaughan, Elizabeth
AU - Smith, Kelly T.
AU - Haden, Kathleen
AU - Hall, Emily H.
AU - Gnjatic, Sacha
AU - Hwu, Patrick
AU - Slingluff, Craig L.
N1 - Funding Information:
Funding SPP has received research support from ImmmunoMet and Oncoceutics; institutional research funding from Bristol Myers Squibb, Deciphera, Foghorn Therapeutics, InxMed, Novartis, Provectus, Reata, and TriSalus Life Sciences; served as IDMC Chair for Immunocore; served as DSMC Chair for Reata; received honoraria as a non-promotional speaker for Merck; served on advisory boards for Cardinal Health, Castle Biosciences, and TriSalus Life Sciences. SG has received grants from Regeneron, BMS, Takeda, and Janssen R&D; personal consulting fees from OncoMed and Merck; and has a patent on NY-ESO-1 peptide formulations. PH has served on advisory boards for Dragonfly and Sanofi; and served as a consultant for Immatics and GlaxoSmithKline. CLS has received institutional research support from Celldex, Glaxo-Smith Kline, Merck, 3M, Theraclion, and Polynoma; served on advisory boards for Immatics and CureVac; received licensing fee payments through the UVA Licensing and Ventures Group for patents for peptides used in cancer vaccines.
Publisher Copyright:
©
PY - 2021/8/19
Y1 - 2021/8/19
N2 - Background We performed a clinical trial to evaluate safety and immunogenicity of a novel long peptide vaccine administered in combinations of incomplete Freund's adjuvant (IFA) and agonists for TLR3 (polyICLC) and TLR7/8 (resiquimod). We hypothesized that T cell responses to minimal epitope peptides (MEPs) within the long peptides would be enhanced compared with prior vaccines with MEP themselves and that T cell responses would be enhanced with TLR agonists, compared with IFA alone. Methods Participants with resected stage IIB-IV melanoma were vaccinated with seven long melanoma peptides (LPV7) from tyrosinase, gp100, MAGE-A1, MAGE-A10, and NY-ESO-1, each containing a known MEP for CD8 + T cells, plus a tetanus helper peptide (Tet) restricted by Class II MHC. Enrollment was guided by an adaptive design to one of seven adjuvant combinations. Vaccines were administered at weeks 1, 2, 3, 6, 9, 12 at rotating injection sites. T cell and IgG antibody (Ab) responses were measured with IFN-gamma ELIspot assay ex vivo and ELISA, respectively. Results Fifty eligible participants were assigned to seven study groups, with highest enrollment on arm E (LPV7+Tet+IFA+polyICLC). There was one dose-limiting toxicity (DLT) in Group E (grade 3 injection site reaction, 6% DLT rate). All other treatment-related adverse events were grades 1-2. The CD8 + T cell immune response rate (IRR) to MEPs was 18%, less than in prior studies using MEP vaccines in IFA. The CD8 + T cell IRR trended higher for IFA-containing adjuvants (24%) than adjuvants containing only TLR agonists (6%). Overall T cell IRR to full-length LPV7 was 30%; CD4 + T cell IRR to Tet was 40%, and serum Ab IRR to LPV7 was 84%. These IRRs also trended higher for IFA-containing adjuvants (36% vs 18%, 48% vs 24%, and 97% vs 60%, respectively). Conclusions The LPV7 vaccine is safe with each of seven adjuvant strategies and induced T cell responses to CD8 MEPs ex vivo in a subset of patients but did not enhance IRRs compared with prior vaccines using short peptides. Immunogenicity was supported more by IFA than by TLR agonists alone and may be enhanced by polyICLC plus IFA. Trial registration number NCT02126579.
AB - Background We performed a clinical trial to evaluate safety and immunogenicity of a novel long peptide vaccine administered in combinations of incomplete Freund's adjuvant (IFA) and agonists for TLR3 (polyICLC) and TLR7/8 (resiquimod). We hypothesized that T cell responses to minimal epitope peptides (MEPs) within the long peptides would be enhanced compared with prior vaccines with MEP themselves and that T cell responses would be enhanced with TLR agonists, compared with IFA alone. Methods Participants with resected stage IIB-IV melanoma were vaccinated with seven long melanoma peptides (LPV7) from tyrosinase, gp100, MAGE-A1, MAGE-A10, and NY-ESO-1, each containing a known MEP for CD8 + T cells, plus a tetanus helper peptide (Tet) restricted by Class II MHC. Enrollment was guided by an adaptive design to one of seven adjuvant combinations. Vaccines were administered at weeks 1, 2, 3, 6, 9, 12 at rotating injection sites. T cell and IgG antibody (Ab) responses were measured with IFN-gamma ELIspot assay ex vivo and ELISA, respectively. Results Fifty eligible participants were assigned to seven study groups, with highest enrollment on arm E (LPV7+Tet+IFA+polyICLC). There was one dose-limiting toxicity (DLT) in Group E (grade 3 injection site reaction, 6% DLT rate). All other treatment-related adverse events were grades 1-2. The CD8 + T cell immune response rate (IRR) to MEPs was 18%, less than in prior studies using MEP vaccines in IFA. The CD8 + T cell IRR trended higher for IFA-containing adjuvants (24%) than adjuvants containing only TLR agonists (6%). Overall T cell IRR to full-length LPV7 was 30%; CD4 + T cell IRR to Tet was 40%, and serum Ab IRR to LPV7 was 84%. These IRRs also trended higher for IFA-containing adjuvants (36% vs 18%, 48% vs 24%, and 97% vs 60%, respectively). Conclusions The LPV7 vaccine is safe with each of seven adjuvant strategies and induced T cell responses to CD8 MEPs ex vivo in a subset of patients but did not enhance IRRs compared with prior vaccines using short peptides. Immunogenicity was supported more by IFA than by TLR agonists alone and may be enhanced by polyICLC plus IFA. Trial registration number NCT02126579.
KW - adjuvants
KW - immunogenicity
KW - immunologic
KW - melanoma
KW - vaccination
KW - vaccine
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U2 - 10.1136/jitc-2021-003220
DO - 10.1136/jitc-2021-003220
M3 - Article
C2 - 34413169
AN - SCOPUS:85113533076
SN - 2051-1426
VL - 9
JO - Journal for immunotherapy of cancer
JF - Journal for immunotherapy of cancer
IS - 8
M1 - 003220
ER -