Immunotherapy with dendritic cells and CpG oligonucleotides can be combined with chemotherapy without loss of efficacy in a mouse model of colon cancer

Abstract

Although immunotherapy has shown promising results in the treatment of cancer, clinical studies assessing immunologic approaches in patients with advanced cancer will seldom be conducted in the absence of conventional treatment strategies such as chemotherapy. Here we investigate the combination of chemotherapy with CpG oligonucleotide and dendritic cell-based immunotherapy in the C26 mouse model of colon carcinoma. The coinjection of antigen-pulsed, mature dendritic cells and CpG oligonucleotides together with a peritumoral injection of CpG oligonucleotides elicits a CD8 T-cell response resulting in tumor rejection and longterm protection in the C26 model. Tumor-bearing mice were treated weekly for 4 weeks by this immunotherapy protocol, by 5-fluorouracil plus leucovorin or irinotecan, or by the combination of immunotherapy and chemotherapy. We observed that immunotherapy was more effective in reducing tumor growth and increasing survival than 5-fluorouracil or irinotecan. Immunotherapy was well tolerated, whereas therapeutic doses of 5-fluorouracil or irinotecan were associated with dose-limiting toxicity. Furthermore, the efficacy of immunotherapy combined with either 5-fluorouracil or irinotecan was similar to that of immunotherapy alone. Addition of immunotherapy to either 5-fluorouracil or irinotecan treatment strongly decreased the toxicity of chemotherapy. Immunotherapy both with and without chemotherapy generated a memory immune response, leading to tumor rejection in mice rechallenged with C26 tumor cells up to several months after treatment. In summary, immunotherapy with a combination of dendritic cells and CpG oligonucleotides is superior to chemotherapy in the C26 tumor model. This immunotherapy protocol can be combined with current chemotherapy agents with no loss in therapeutic activity. ' 2005 Wiley-Liss, Inc.

TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours

“…Tumour antigen can be loaded onto DCs in a number of forms, including killed tumour cells, whole tumour supernatants, lysates, purified tumour-specific antigens and synthetic peptides (Banchereau and Palucka, 2005). Maturation of the DC can be induced by stimulation with cytokines such as IL-1b and tumor necrosis factor-a in combination with PGE2 (Dannull et al, 2005) or with TLR agonists (Bourquin et al, 2006). The first DC vaccine trials in humans took place over a decade ago, where follicular B-cell lymphoma patients were injected with DCs pulsed in vitro with tumourspecific idiotype protein purified from the patient's own tumour (Hsu et al, 1996).…”

“…Furthermore, DC pulsed with tumour antigen and CpG at a distant site to the tumour combined with peritumoral injection of CpG resulted in regression of large murine tumours resistant to chemotherapy (Heckelsmiller et al, 2002a). It has also been demonstrated that injection of DCs pulsed with antigen (irradiated tumour cells) and CpG is effective at treating established C26 tumours in mice (Bourquin et al, 2006). Therapeutic administration of DC pulsed with a human papillomavirus-16-derived peptide mixed with CpG-ODN resulted in eradication of HPV-16-expressing tumours in mice (Zwaveling et al, 2002).…”

MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model

“…The net effect of TLR9 activation is to induce Th1 biased cellular and humoral effector functions with strong CTL generation [33]. In murine models of cancer and in phase I/II clinical trials in patients with metastatic melanoma and non-small cell lung cancer, CpG ODN has improved tumor responses to conventional therapies such as chemotherapy, radiotherapy, and immunotherapy [34][35][36][37][38][39][40][41]. GM-CSF is a commercially available cytokine currently used in patients undergoing chemotherapy to shorten the duration of post-chemotherapy neutropenia.…”

Radiation therapy and Toll-like receptor signaling: implications for the treatment of cancer

“…Conversely, TLR-targeted therapy may enhance subsequent responses to chemotherapy. Such combinations have been explored in a number of preclinical studies, sometimes with promising results (Lake and Robinson, 2005;Bourquin et al, 2006;Shi et al, 2007). For example, Shi et al (2007) demonstrated enhanced chemo-sensitivity of chronic lymphocytic leukemia cells after tolerizing treatment with the TLR7 agonist, S28690.…”