CpG oligodeoxynucleotides as immunotherapy in cancer

Abstract

Preclinical and early clinical trials indicate synthetic oligodeoxynucleotides containing unmethylated CG dinucleotides (CpG ODN) have potent immunostimulatory effects and can enhance the anticancer activity of a variety of cancer treatments. Synergy between CpG ODN and monoclonal antibodies has been noted in various preclinical models. Early clinical trials indicate CpG ODN and monoclonal antibodies can be administered safely together. Preclinical models indicate CpG ODN can enhance the anti-tumor activity of both chemotherapy and radiation therapy. Thus, one possible approach to the use of CpG ODN was to use it in combination with cytotoxic chemotherapy with the goal of enhancing presentation of tumor antigen from dying cancer cells. Promising results in a randomized phase II trial in patients with non-small cell lung cancer led to initiation of two large randomized phase III trials comparing CpG ODN plus chemotherapy to chemotherapy alone. Unfortunately, interim analysis of these trials indicated CpG ODN was unlikely to enhance efficacy of chemotherapy, and they were stopped. CpG ODN also holds promise as a component of cancer vaccines including those composed of protein antigen, peptides, whole tumor cells, and antigenpulsed dendritic cells. Finally, CpG ODN has been combined with a variety of cytokines to enhance NK activation, promote development of an active anti-tumor immune response or induce apoptosis of malignant cells that express the TLR9 receptor. Overall, both preclinical and early clinical trials suggest CpG ODN may be a valuable component of a variety of approaches to cancer therapy. However, clinical development of this recently discovered, novel class of immunostimulatory agents is just beginning, and we still have much to learn about the optimal approach to their use, and their potential.

Acute lymphoblastic leukemia cells treated with CpG oligodeoxynucleotides, IL-4 and CD40 ligand facilitate enhanced anti-leukemic CTL responses

“…22 Moreover, even in-vitro, CpG alone often fails to trigger robust cellular immune responses against immunogenized leukemic cells. Therefore, the combined use of CpG with other B-cell stimulatory agents may significantly boost the immunogenic effect of CpG alone, 23 particularly when an ex-vivo approach is selected, where higher concentrations of such B-cell stimulatory agents may be used without the danger of adverse effects on other cells or the whole organism. Here, we demonstrate that the combination of CpG, CD40L and IL-4 is highly effective in inducing BCP-ALL immunogenicity, thereby exceeding the effect of CpG alone.…”

Plasmacytoid Dendritic Cells Alter the Antitumor Activity of CpG-Oligodeoxynucleotides in a Mouse Model of Lung Carcinoma

“…Despite advances in treatment, the prognosis remains poor, with only 15% of patients surviving more than five years from time of diagnosis. Lung carcinoma is a nonimmunogenic cancer (1,2), which renders it more resistant to immune surveillance. Activation of the immune system could, therefore, represent a means to induce tumor regression (2,3).…”

CD1b-autoreactive T cells recognize phospholipid antigens and contribute to antitumor immunity against a CD1b+T cell lymphoma

“…Interestingly, both CpG and IL-12 have been used in pre-clinical studies as anticancer therapy. 38,46 Both these immunostimulatory agents work to increase the production of IFNg by innate and adaptive immune cells. However, clinical trials have yielded mixed results, mostly due to over stimulation of the immune system and related adverse side effects or the lack of apparent benefits over existing treatment options.…”

“…However, clinical trials have yielded mixed results, mostly due to over stimulation of the immune system and related adverse side effects or the lack of apparent benefits over existing treatment options. 38,46 Nevertheless, recent efforts have been directed toward delivering these agents to the local tumor microenvironment and in conjunction with other immunotherapies like T cell adoptive transfer.…”

“…Our previous study showed that extracellular TLR ligands enhanced HJ1 T cell autoreactivity. 35 Thus, we examined whether CpG ODN, an intracellular TLR 9 agonist, known to have antitumor effects, 38 could enhance HJ1 T cell autoreactivity. We also compared the effect of other TLR agonists on the reactivity of HJ1 T cells.…”