Dendritic Cell-Mediated Cross-Presentation of Antigens Derived from Colon Carcinoma Cells Exposed to a Highly Cytotoxic Multidrug Regimen with Gemcitabine, Oxaliplatin, 5-Fluorouracil, and Leucovorin, Elicits a Powerful Human Antigen-Specific CTL Response with Antitumor Activity in Vitro

Abstract

Gemcitabine, oxaliplatin, leucovorin, and 5-fluorouracil (GOLF) is a novel multidrug regimen inducing high levels of necrosis and apoptosis in colon carcinoma cells. This regimen is also able to promote a process of Ag remodeling including up-regulation of immunotherapy targets like carcinoembryonic Ag (CEA), thymidylate synthase (TS). We have conducted a preclinical study aimed to investigate whether these drug-induced modifications would also enhance colon cancer cell immunogenicity. Several CTL lines were thus generated by in vitro stimulating human HLA-A(*)02.01+ PBMCs, from normal donors and colon cancer patients, with autologous dendritic cells cross-primed with cell lysates of colon cancer cells untreated, irradiated, or previously exposed to different drug treatments including the GOLF regimen. Class I HLA-restricted cytolytic activity of these CTL lines was tested against colon cancer cells and CEA and TS gene transfected target cells. These experiments revealed that CTLs sensitized with GOLF-treated cancer cells were much more effective than those sensitized with the untreated colon carcinoma cells or those exposed to the other treatments. CTL lines sensitized against the GOLF-treated colon cancer cells, also expressed a greater percentage of T-lymphocyte precursors able to recognize TS- and CEA-derived peptides. These results suggest that GOLF regimen is a powerful antitumor and immunomodulating regimen that can make the tumor cells a suitable means to induce an Ag-specific CTL response. These results suggest that a rationale combination of GOLF chemotherapy with cytokine-based immunotherapy could generate a chemotherapy-modulated Ag-specific T-lymphocyte response in cancer patients able to destroy the residual disease survived to the cytotoxic drugs.

Chitosan hydrogel containing GMCSF and a cancer drug exerts synergistic anti-tumor effects via the induction of CD8+ T cell-mediated anti-tumor immunity

“…T cells [44][45][46]. As has been noted in the literature, many chemotherapeutic agents have been shown to slightly increase the anti-tumor immune response via the cross-presentation of an apoptotic tumor body, mediated by caspase activation [24,25,[47][48][49][50]. On the basis of this observation, we believe that CH-CTX ?…”

Phase I trial of thymidylate synthase poly-epitope peptide (TSPP) vaccine in advanced cancer patients

“…This phase Ib trial evaluated the safety and biological activity of TSPP administered alone or in combination with an immune-adjuvant regimen (IG-1) containing granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-2 [15], in advanced cancer patients. The rationale to combine TSPP with IG-1 regimen derived from preclinical in vitro findings [12,14,16,17] and previous clinical studies, where the IG-1 regimen alone [15] or in combination with 5′FU-based chemotherapy was found to be safe, able to generate activated dendritic cells (DCs) and to promote an efficient antigen-specific T cell response [18,19].…”

Phase Ib study of poly-epitope peptide vaccination to thymidylate synthase (TSPP) and GOLFIG chemo-immunotherapy for treatment of metastatic colorectal cancer patients

“…We already demonstrated that tumor cell exposure to GOLF regimen increases the expression of multiple TAA (like TS, CEA, and EGFR), enhances the expression of danger signals and "eat-me" molecules, and induces immunogenicity in colon and breast cancer cell models in vitro. 9,13,14,[16][17][18][19] These preclinical findings provided a clear rationale to investigate the GOLF regimen in combination with an immune-adjuvant IG-1 cytokine regimen (sc. Interleukin (IL)-2 and sc.…”