A phase I vaccination study with dendritic cells loaded with NY-ESO-1 and α-galactosylceramide: induction of polyfunctional T cells in high-risk melanoma patients

Abstract

Vaccines that elicit targeted tumor antigen-specific T-cell responses have the potential to be used as adjuvant therapy in patients with high risk of relapse. However, the responses induced by vaccines in cancer patients have generally been disappointing. To improve vaccine function, we investigated the possibility of exploiting the immunostimulatory capacity of type 1 Natural killer T (NKT) cells, a cell type enriched in lymphoid tissues that can trigger improved antigen-presenting function in dendritic cells (DCs). In this phase I dose escalation study, we treated eight patients with high-risk surgically resected stage II-IV melanoma with intravenous autologous monocyte-derived DCs loaded with the NKT cell agonist α-GalCer and peptides derived from the cancer testis antigen NY-ESO-1. Two synthetic long peptides spanning defined immunogenic regions of the NY-ESO-1 sequence were used. This therapy proved to be safe and immunologically effective, inducing increases in circulating NY-ESO-1-specific T cells that could be detected directly ex vivo in seven out of eight patients. These responses were achieved using as few as 5 × 10 peptide-loaded cells per dose. Analysis after in vitro restimulation showed increases in polyfunctional CD4 and CD8 T cells that were capable of manufacturing two or more cytokines simultaneously. Evidence of NKT cell proliferation and/or NKT cell-associated cytokine secretion was seen in most patients. In light of these strong responses, the concept of including NKT cell agonists in vaccine design requires further investigation.

Nanovaccine administration route is critical to obtain pertinent iNKt cell help for robust anti-tumor T and B cell responses

“…Given the fact that iNKT cells are mainly found in spleen and liver, it is logical to anticipate a higher impact upon intravenous (iv) administration as it was performed in multiple preclinical tumor models and early phase I clinical trials. 14,[28][29][30] Nevertheless, several groups also applied other administration routes and some claim to obtain better iNKT cell and NK cell activation than iv injections. 7,[16][17][18][31][32][33] Besides, the iNKT mediated help over antigen-specific T and B cell responses has not been compared in different immune compartments and administration routes.…”

The Role of Natural Killer T Cells in Cancer—A Phenotypical and Functional Approach

“…Another strategy that was suggested for the treatment of patients with solid tumors is vaccination with NKT-activating agents in combination with tumor antigens. For instance, a phase I study showed detectable NKT cell activity in patients with high-risk melanoma upon treatment with cancer/testis antigen-loaded DC in combination with α-GalCer ( 261 ). However, in our opinion, increasing the specificity of NKT cells is not the most promising method of increasing the effectiveness of NKT-based immunotherapies.…”

Improving Immunotherapy Through Glycodesign

“…Notably, multiple antibodies are in preclinical and clinical trials that target GSLs including GD2 ( 169 ), GM2 ( 170 ), Neu5GcGM3 ( 171 ), Gb3, Gb4, and Globo H ( 172 ). Another GSL, α-GalCer, has potential anti-tumor activity and is currently in phase 1 clinical trials in high risk melanoma patients ( 173 ).…”