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 anti-cancer 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 antigen-pulsed 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.

Figure 1. Mechanisms by which CpG ODN may contribute to cancer immunotherapy

CpG ODN can enhance tumor antigen presentation and T cell response when administered as an adjuvant with cancer vaccines or following antigen release induced by standard cytotoxic treatments such as chemotherapy or radiation. CpG ODN can induce production from dendritic cells of cytokines such as IFN alpha which activate NK cells. The activated NK cells then mediate enhanced antibody dependent cellular cytotoxicity or direct killing of NK sensitive cancers. CpG ODN can also lead directly to activation-induced cell death of TLR9 positive B cell malignancies.