Resiquimod as an Immunologic Adjuvant for NY-ESO-1 Protein Vaccination in Patients with High-Risk Melanoma

Abstract

The TLR7/8 agonist, Resiquimod has been used as an immune adjuvant in cancer vaccines. We evaluated the safety and immunogenicity of the cancer testis antigen NY-ESO-1 given in combination with Montanide with or without Resiquimod in high-risk melanoma patients. In Part I of the study, patients received 100ug full length NY-ESO-1 protein emulsified in 1.25mL Montanide (day 1) followed by topical application of 1000mg of 0.2% Resiquimod gel on days 1 and 3 (Cohort 1) versus days 1, 3, and 5 (Cohort 2) of a 21 day cycle. In Part II, patients were randomized to receive 100ug NY-ESO-1 protein plus Montanide (day 1) followed by topical application of placebo gel (Arm-A; N=8) or 1000mg of 0.2% Resiquimod gel (Arm-B; N=12) using the dosing regimen established in Part I. The vaccine regimens were generally well-tolerated. NY-ESO-1-specific humoral responses were induced or boosted in all patients, many of whom had high titer antibodies. In Part II, 16 of 20 patients in both arms had NY-ESO-1-specific CD4+ T-cell responses. CD8+ T-cell responses were only seen in 3 of 12 patients in Arm B. Patients with TLR7 SNP rs179008 had a greater likelihood of developing NY-ESO-1-specific CD8+ responses. In conclusion, NY-ESO-1 protein in combination with Montanide with or without topical Resiquimod is safe and induces both antibody and CD4+ T-cell responses in the majority of patients; the small proportion of CD8+ T-cell responses suggests that the addition of topical Resiquimod to Montanide is not sufficient to induce consistent NY-ESO-1-specific CD8+ T-cell responses.

Decitabine Enhances Lymphocyte Migration and Function and Synergizes with CTLA-4 Blockade in a Murine Ovarian Cancer Model

“…Of the cancers investigated to date, this effect is most pronounced in ovarian cancer cells (16). Treatment of ovarian cancer cells with the DNA methyltransferase inhibitor DAC (17) results in expression of cancer-testis antigens and MHC class I, increasing cancer cell recognition by CD8 þ T cells (18). DAC similarly restores expression of cytokines, cancer-testis antigens, MHC class I and II, and costimulatory molecules in cancer patients (19,20).…”

Trial watch: Peptide-based vaccines in anticancer therapy

“…Peptide-based vaccination was employed as a standalone adjuvanted intervention, 140-146 or combined with chemotherapy 147-149 radiation therapy 147,150 or other forms of treatment including other immunotherapies. 148,149,151-158 These studies enrolled patients with hematological malignancies, 151,159 brain tumors, 152,153 non-small cell lung carcinoma (NSCLC), 140,147,160 breast cancer, 141,148,161 , prostate carcinoma, 142,154 melanoma, 144-146,155-158,162 . ovarian cancer.…”

“…149 , cervical cancer, 163 hepatocellular carcinoma 164 and biliary tract cancer 165 . The TAAs harnessed for the construction of peptide-based vaccines in these studies included the cancer/testis antigen 1B (CTAG1B; best known as NY-ESO-1), 144 MAGE family member A3 (MAGEA3), 140,146,147 TTK protein kinase (TTK), 158 WT1, 151,166 baculoviral IAP repeat containing 5 (BIRC5; best known as survivin), 149 mutant epidermal growth factor receptor (EGFRvIII), 153 erb-b2 receptor tyrosine kinase 2 (ERBB2; best known as HER2), 148 indoleamine 2,3 dioxygenase 1 (IDO1), 157 TCR gamma alternative reading frame protein (TARP), 154 and multiple glioma-associated antigens. 152 Most often, peptide-based vaccines were well tolerated and no severe side effects were reported.…”

“…Mild side effects were sporadic and included flu-like symptoms, fatigue and minor reactions at the injection site. Immunes responses driven by vaccination were documented in a variety of studies based on (1) interferon gamma (IFNG) production by T cells with enzyme-linked immunospot (ELISPOT) assays, 142,151,152,154,155 (2) tumor infiltration by CD4 + and CD8 + lymphocyte infiltration, 144,145,147,157,158 or (3) presence of peptide-specific antibodies in the serum. 158 Sporadic clinical responses were also documented (see below).…”

Toll-like receptors and cutaneous melanoma

“…Furthermore, by contrast to imiquimod, resiquimod may be orally administered (60). Resiquimod may be considered as a potential cancer vaccine adjuvant due to its ability to increase antigen presentation via the direct activation of dendritic cells (DCs), determine local activation of immune cells and enhance the production of pro-inflammatory cytokines and the subsequent transcription of NF-κB and type I IFN (62). A previous study revealed that combined treatment with NY-ESO-1 antigens (a frequently expressed tumor-specific antigen that stimulate humoral and cellular immune responses in cancer patients), Montanide (an immune adjuvant that ensures the slow release of antigens and the recruitment of antigen-presenting cells to the injection site) and topical resiquimod results in high immunogenicity in melanoma patients.…”