CpG oligodeoxynucleotide-based therapy of lymphoid malignancies☆

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Abstract

Preclinical and early clinical trials indicate synthetic oligodeoxynucleotides containing unmethylated CG dinucleotides (CpG ODN) have potent immunostimulatory effects. CpG ODN are being explored as immune adjuvants in vaccination strategies and as potential treatments for a wide variety of disorders including cancer and asthma. Therapeutic approaches designed to take advantage of this potent class of agents are based largely on the ability of CpG ODN to activate professional antigen presenting cells (APCs) that express the target receptor — Toll-Like Receptor 9 (TLR9). B-cell malignancies are unique in that the malignant cells themselves express TLR9. CpG ODN can have a direct effect on the malignant B cells and lead to activation induced cell death. CpG ODN also alter the phenotype of target malignant B cells as indicated by upregulation of MHC, immunostimulatory molecules, and antigens that serve as targets for other approaches to lymphoma immunotherapy such as CD20. B cell malignancies are also relatively sensitive to the cytokines that are produced by dendritic cells in response to CpG ODN. Thus, B cell malignancies appear to be uniquely sensitive to CpG ODN because of both the direct and indirect effects the CpG ODN on target cells and the sensitivity of B cell malignancies to an immune response. Preclinical studies support further exploration of the potential of CpG ODN as a component of therapy for lymphoid malignancies. Ongoing clinical trials are exploring the potential of CpG ODN, both alone and in combination with other agents.

Introduction

Over a hundred years have passed since the first anti-tumor effects of bacteria were identified by New York surgeon Dr. William Coley [1]. We now know that receptors in vertebral immune systems can recognize prokaryotic products that contain molecular patterns, and that such pattern receptors represent an important component of the innate immune response to prokaryotic infection. The prokaryotic bacterial DNA itself is one such molecular pattern, and has immunostimulatory properties due to sequence characteristics that are distinct from those found in eukaryotic DNA [2]. Multiple studies have demonstrated that bacterial DNA, and synthetic oligodeoxynucleotides that contain unmethylated CG dinucleotides and a phosphorothioate or chimeric backbone that renders them nuclease resistant (CpG ODN), have potent immunostimulatory effects. The pattern recognition receptor Toll-Like Receptor 9 (TLR 9) has been found to be the primary receptor for CpG ODN. The complex immunologic responses to CpG ODN by various immune cell subsets involve both direct effects mediated by TLR9 and indirect effects, resulting in the activation of NK cells, T cells, B cells, monocytes, macrophages and dendritic cells. The immunostimulatory effects of CpG ODN, and the therapeutic potential of this class of agents in cancer and other diseases, has been under investigation for the past decade, and are reviewed in detail elsewhere in this volume. B-cell malignancies are unique in that the target cells express TLR9. Lymphomas also tend to be more sensitive to cytokines and immune-based therapies than other malignancies [3]. Here, we provide a review of what is known about CpG ODN as a therapeutic agent for the treatment of lymphoid malignancies with a focus on B cell malignancies.

Section snippets

CpG ODN induced proliferation of malignant B cells

The description of the immunostimulatory effects of bacterial DNA and CpG ODN that reinvigorated our interest in the immunostimulatory effects of ODN described its anti-apoptotic effects on benign B cells [2]. It would seem counter intuitive to hypothesize that a class of agents that prevents apoptosis of B cells would be useful to treat malignant B cells. However, activation induced cell death has been well described as a mechanism that limits immune overstimulation. Thus, agents that

CpG ODN and activation induced cell death

As mentioned above, in the B cell malignancies, short term proliferation can lead to activation induced cell death. We found CpG ODN decreased numbers of viable CLL cells and increased numbers of apoptotic cells after 4 days when compared to control ODN or no ODN in 13 out of 20 primary CLL samples [11]. Cytogenetics impacted on response. Those subjects with good prognosis CLL cytogenetics were more likely to undergo apoptosis in response to CpG ODN than were subjects with poor prognosis

CpG ODN induced changes in immunophenotype of B cell malignancies

CpG ODN has other effects on malignant B cells that could impact on therapeutic response. CpG ODN 2006 can increase the expression of costimulatory molecules (CD40, CD80, CD86, CD54) on a variety of primary human malignant B cells [22]. CpG ODN also enhances expression of class I and class II MHC in most samples. In mixed lymphocyte reactions, CpG ODN markedly increased the T cell response to malignant B cells.

CpG ODN can also impact on expression of receptors for cytokines. Decker et al. found

CpG ODN and anti-CD20-based therapy

Anti-CD20 monoclonal antibody therapy has changed the way we treat B cell malignancies [25]. Rituximab, a chimeric anti-CD20 monoclonal antibody, is now a mainstay of treatment for the B cell malignancies. We and others have found that in vitro CpG ODN treatment of a variety of B cell malignancies increases expression of CD20 by the malignant cells [5], [22]. These studies demonstrated an inverse correlation between baseline expression of CD20 and its expression after exposure to CpG ODN, thus

Enhancing the immune response

Use of CpG ODN as immune adjuvants is outlined elsewhere in this volume and will not be reviewed in detail here. However, it is worth mentioning that cancer vaccine approaches have been studied in lymphoid malignancies, and CpG ODN has been shown to be a potent adjuvant in preclinical models of lymphoma [30], [31].

Given that CpG ODN enhances the immune response, and lymphomas tend to be sensitive to cytotoxic therapy, the combination of CpG ODN and cytotoxic therapy holds promise. This is based

CpG ODN-induced cytokines and lymphoid malignancy

Interferon alpha has been studied extensively as a treatment for both B and T cell lymphoma. When administered in purified or recombinant form, interferon alpha has clear anti-lymphoma activity in both B cell and T cell lymphoid malignancies when used alone and in combination with other agents [32], [33]. CpG ODN induce production by pDCs of a wide variety of cytokines including interferon alpha. Thus, secondary production of cytokines, including but not limited to interferon alpha, could

Class of CpG ODN and route of administration

Data to date raise interesting and unanswered questions concerning which class of CpG ODN, and which route of administration, is likely to be most effective as a treatment for lymphoid malignancies. As outlined elsewhere in this volume, there are different classes of CpG ODN. A-class CpG ODN are potent inducers of IFN alpha production, while B-class CpG ODN are strong stimulators of B cell responses. C-class CpG ODN have effects similar to the A and B classes. They activate B cells and induce

Summary

CpG ODN can mediate anti-tumor effects on lymphoid malignancies due to direct effects on cell viability, indirect effects due to CpG ODN-induced cytokines, and immunologic effects that result from enhanced development of an immune response (Fig. 1). Many lymphoid malignancies express TLR9 and, after a brief period of proliferation, have a tendency to undergo activation induced cell death in response to CpG ODN. Lymphoid malignancies are also sensitive to cytokines produced in response to CpG

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    ☆

    This review is part of the Advanced Drug Delivery Reviews theme issue on “CpG Oligonucleotides as Immunotherapeutic Adjuvants: Innovative Applications and Delivery Strategies”.

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