Rapid Induction of Tumor-specific Type 1 T Helper Cells in Metastatic Melanoma Patients by Vaccination with Mature, Cryopreserved, Peptide-loaded Monocyte-derived Dendritic Cells

Abstract

There is consensus that an optimized cancer vaccine will have to induce not only CD8+ cytotoxic but also CD4+ T helper (Th) cells, particularly interferon (IFN)-γ–producing, type 1 Th cells. The induction of strong, ex vivo detectable type 1 Th cell responses has not been reported to date. We demonstrate now that the subcutaneous injection of cryopreserved, mature, antigen-loaded, monocyte-derived dendritic cells (DCs) rapidly induces unequivocal Th1 responses (ex vivo detectable IFN-γ–producing effectors as well as proliferating precursors) both to the control antigen KLH and to major histocompatibility complex (MHC) class II–restricted tumor peptides (melanoma-antigen [Mage]-3.DP4 and Mage-3.DR13) in the majority of 16 evaluable patients with metastatic melanoma. These Th1 cells recognized not only peptides, but also DCs loaded with Mage-3 protein, and in case of Mage-3DP4–specific Th1 cells IFN-γ was released even after direct recognition of viable, Mage-3–expressing HLA-DP4+ melanoma cells. The capacity of DCs to rapidly induce Th1 cells should be valuable to evaluate whether Th1 cells are instrumental in targeting human cancer and chronic infections.

Adenovirus hexon T-cell epitope is recognized by most adults and is restricted by HLA DP4, the most common class II allele

“…For instance, dendritic cells loaded with the MAGE 3 HLA DP4 peptide have recently been shown to induce T-helper cell responses in a majority of patients with metastatic melanoma. 17 Additionally, this hexon epitope was recognized by all donor sera and thus represents a B-cell epitope. Sera from most individuals contain multiple antibodies to hexon, including serotype-specific neutralizing antibodies targeted to variable regions on the external surface of the molecule.…”

Comparison of recombinant adenovirus and synthetic peptide for DC-based melanoma vaccination

“…First published reports provided proof-of-principle for this vaccine strategy using DC. 27,28 However, clinical results were variable. Notably, long-lasting clinical responses in individual patients were reported in several studies.…”

Dendritic Cells Charged with Apoptotic Tumor Cells Induce Long-Lived Protective CD4+ and CD8+ T Cell Immunity against B16 Melanoma

“…With increased understanding of the requirements for initiating immunity, dendritic cells (DCs) 3 have become attractive vectors for immunotherapy of this and other cancers (2)(3)(4)(5)(6)(7)(8)(9). DCs are proving to be effective in initiating and expanding immune responses in humans (10,11), providing a rationale for their use as adjuvants for active immunization against melanoma (12)(13)(14)(15)(16). Different strategies have been developed to load DCs with tumor Ags, including MHC-restricted synthetic peptides derived from the Ag (12)(13)(14)(15)(16)(17), tumor RNA (18,19), tumor lysates (20), tumor-derived exosomes (21), and dying tumor cells (22)(23)(24)(25)(26); these have been assessed in preclinical models and, in some cases, clinical trials (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)…”