Daniel J. Lindner
Kevin L. Taylor
Frederic J. Reu
Paul A. Masci
Ernest C. Borden
Interferon-α (IFN-α) was the first human protein effective for cancer treatment and the first economically important clinical product for cancer developed from recombinant DNA technology. IFNs have been prototypes for the clinical development of other immunomodulatory and growth-regulatory cytokines. IFN-α2, one IFN-α family member, has proven effective not only as an antitumor protein but also for antiviral therapy. The complex biologic and therapeutic activities of IFNs include virus inhibition, immunomodulation, slowing of cell proliferation, oncogene suppression, angiogenesis inhibition, alterations in differentiation, and induction of other cytokines (Table 32.1). Reflecting the pleiotropic biological effects, IFN-β has proven effective for slowing disease progression and relapses in multiple sclerosis and IFN-γ for intracellular pathogens.1, 2, 3, 4
Modulation of gene expression, which is reviewed below, must underlie the clinical activities of IFNs. An important regulatory pathway for gene induction, the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway, was originally elucidated by the study of IFNs but has proven to be critical for signaling by other cytokines and growth factors. Dissection of signal transduction pathways has enabled beginning dissection of the mechanisms of therapeutic resistance. The IFN-induced proteins that mediate these activities have only been partially identified.5
In seven malignancies, IFN-α2 results in regression or control of disease processes (Table 32.2). The spectrum of single-agent activity of IFNs compares favorably with other systemic cancer treatment modalities. The antitumor effects of IFNs can be enhanced in experimental tumor models by cytotoxic compounds, radiation, and other biologics. Greater clinical benefit will undoubtedly result through the use of IFNs in combination with other treatments, a topic beyond the scope of this chapter but dependent on understanding IFNs' effects as single agents.
INTERFERONS: THEIR STRUCTURE AND INDUCERS
Like many other cytokines, the IFNs are a family of proteins that include more than a dozen different members encoded on human chromosome 9p (except IFN-γ which is encoded on human chromosome 12q) (Table 32.3). The biologic and clinical significance of the individual proteins encoded by the approximately 15 distinct nonallelic IFN-α genes has barely been studied. These individual proteins differ over a 50-fold range in their potency in eliciting antiproliferative, immunomodulatory, and antiviral cellular effects.6 Other than IFN-α2, the only IFN-α gene product generated for clinical research trial has been IFN-α1, which has proven to be better tolerated than IFN-α2.7 The three major classes of IFNs (α, β, γ) were initially defined on the basis of their chemical, antigenic, and biologic variation. These variations result from differences in their primary amino acid sequences. Complete nucleotide sequences have been determined for almost 20 human IFNs.8, 9, 10, 11 IFN-α and IFN-β have approximately 45% nucleotide homology and 29% amino acid homology. Each of the nonallelic human IFN-α genes differs by approximately 10% in nucleotide sequence and 15 to 25% in amino acid sequence (Table 32.3). IFN-γ, 143 amino acids in length, is located on chromosome 1211, 12 and has only minimal sequence homology with IFN-α or IFN-β. Three additional IFN classes, ω, λ, and τ, have been defined. IFN-ω and IFN-λ bind to the same receptor as IFN-α and IFN-β and mediate similar biologic effects.13, 14 IFN-τ is a novel class of IFN, identified in domestic ruminants but not humans, that maintains the appropriate milieu in the endometrium for trophoblastic implantation.15, 16 Despite the glycosylation of endogenous IFN-β and IFN-γ, the biologic effects of the unglycosylated proteins produced in Escherichia coli have been shown to be similar.17 The glycosylated and unglycosylated IFNs inhibit the replication of RNA and DNA viruses. Second-generation IFN molecules, bioengineered for potentially desirable effects, have now entered clinical trials in oncology. One of these has been approved for use in chronic active hepatitis.18, 19, 20
TABLE 32.1 BIOLOGIC EFFECTS OF INTERFERONS
TABLE 32.2 INTERFERONS: INTERNATIONALLY APPROVED INDICATIONS
TABLE 32.3 MOST COMMON INTERFERON FAMILY MOLECULES
In addition to the direct administration of IFNs, chemically defined IFN inducers may have several therapeutic applications. They may possess advantageous pharmacokinetics for IFN induction, directly induce additional cytokines, activate immune effector cells, and, if administered orally, be more convenient. In some clinical settings, they might prove more effective as therapeutic agents, in addition to potentially being chemopreventive. The first chemically defined inducers of IFNs were double-stranded polyribonucleotides, such as polyriboinosinic-polyribocytidilic acid (poly I:poly C), now known to induce IFNs through activation of toll-like receptor 3 (TLR3). Although potent IFN inducers and immunomodulators in mice, poly I:poly C and various modifications do not consistently induce IFN or have any antitumor activity in humans at clinically tolerable doses.21 Subsequently, low molecular weight organic compounds, such as tilorone, halopyrimidinones, acridines, substituted quinolones, and flavone acetic acid, were identified as inducers of IFNs in different animal species. Several IFN inducers have been introduced into human clinical trials, and some induce substantial amounts of IFN and activate the IFN system.22, 23, 24, 25, 26Imiquimod, a low molecular weight compound, and CpG7909, a phosphorothioate oligodeoxyribonucleotide, activate TLR8 and TLR9, respectively.27, 28, 29, 30Emerging data suggest that these IFN and cytokine inducers may have clinically useful therapeutic activity.
INTERFERON SIGNALING AND RESISTANCE MECHANISMS
Signal Transduction and Control of Interferon-Stimulated Gene Expression
Cellular responses to IFNs are initiated by ligand binding to specific plasma membrane receptors.31 These receptors have been characterized using genetic, biochemical, and molecular biologic approaches.32 The following sections focus on IFN receptors, the mechanisms by which IFN-stimulated genes (ISGs) are induced, and the genes regulated by IFNs.
IFN receptors lack intrinsic enzymatic activity31 but instead are associated with cytoplasmic tyrosine kinases of the JAK family (JAK kinases, including JAK1, JAK2, JAK3, and Tyk2).31, 33 Following IFN binding to its receptor, the JAK kinases phosphorylate tyrosine residues on latent cytoplasmic transcriptional factors, designated “signal transducers and activators of transcription” (STATs), which migrate to the nucleus and induce transcription of IFN-stimulated genes (Fig. 32.1).31, 34
IFN-α, IFN-β and IFN-ω bind to a common IFN receptor (type I), whereas IFN-γ binds to a distinct receptor (type II).35 The two types of IFN receptors are found on the cells of all normal and malignant tissues36 and possess equilibrium dissociation constants (KD) between 10-11 and 10-9 M. The number of receptors is between 100 and 2,000 per cell. Type I and type II receptors are transmembrane glycoproteins (Fig. 32.1).
Two subunits of the type I IFN receptor, IFNAR-137 and IFNAR-238, 39 have been cloned. They associate with Tyk2 (tyrosine kinase 2) and JAK1 kinases, respectively.40, 41 The genes encoding the two subunits are located in the q22.1 region of human chromosome 21.40, 41, 42 Human IFNAR-1 and IFNAR-2, when expressed in mouse cells, confer antiviral activity in response to type I human IFNs.43 The failure of human IFNAR-1 and IFNAR-2 to confer on mouse cells the antiproliferative activity of human type I IFNs suggests the involvement of additional molecules in the receptor complex.43
The IFN-γ receptor has two subunits, IFNGR-1 and IFNGR-2,44, 45, 46 which are associated with the JAK1 and JAK2 kinases, respectively.47, 48 In humans, IFNGR-1 is located on chromosome 6q.44 IFN-γ binds to IFNGR-1, inducing IFNGR-1 dimerization and association with IFNGR-2 to activate the receptor-coupled JAK1 and JAK2 kinases in transducing signals.47
IFNs, like many other cytokines, activate protein tyrosine kinases to transduce signals. The lack of protein tyrosine kinase domains in IFN receptors indicated that additional receptor or nonreceptor protein tyrosine kinases must be involved.38, 39, 44, 45, 46 Complementation of IFN-resistant mutant cell lines by genes coding for members of the JAK kinases provided direct evidence that JAK1, JAK2, and Tyk2 are required for signal transduction. A mutant cell line that lacked the ability to respond to IFN-α or IFN-γ became responsive to IFNs when the JAK1 kinase was expressed in the mutant,49 indicating the central role of JAK1 in IFN-α and IFN-γ signaling pathways. Complementation of an IFN-γ nonresponsive mutant (IFN-α and IFN-β response intact) with the gene for JAK2 demonstrated the requirement for JAK2 in the IFN-γ response.50 Complementation of an IFN-α nonresponsive mutant (IFN-γ response intact) with the gene for Tyk2 demonstrated that Tyk2 is essential for the IFN-α response.51 Biochemical studies demonstrated that each subunit of the IFN receptors associates specifically with a JAK family kinase (Fig. 32.1) that is activated by IFN binding to the receptors, resulting in phosphorylation of tyrosine residues of cellular proteins, including STATs.
Figure 32.1 Components of the interferon (IFN) signaling pathways. The major components responsible for relaying IFN-mediated signals from the cell surface to the regulatory elements of IFN-stimulated genes are represented. GAS, IFN-γ activated site; IFNAR, IFN-α receptor; IFNGR, IFN-γ receptor; ISRE, IFN-stimulated response element; JAK, Janus kinase; SHP, src-homology 2 domain–containing protein tyrosine phosphatase; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription; Tyk, JAK family kinase. Small black bars represent tyrosine residues that become phosphorylated and induce complex formation.
The STAT family of proteins transduce signals from a variety of cell surface receptors to the nucleus and activate transcription by binding to DNA regulatory elements.31 Each of the STATs has a dimerization domain at its N-terminal region, an IFN-regulatory factor (IRF)–binding domain, a DNA-binding domain, SH2 and SH3 domains, and a C-terminal transcription activation domain.34 The JAK kinases, when activated by IFN binding to the receptors, undergo autophosphorylation, transphosphorylate each other, and phosphorylate the receptor subunits.33 The phosphorylated tyrosine residues in these proteins provide binding sites for the SH2 domains of STATs, resulting in STAT recruitment to the receptor and JAK complexes and the phosphorylation of tyrosine residues in the STATs.31 This leads to STAT dimerization, translocation to the nucleus, and binding to promoter elements to control the transcription of IFN-stimulated genes.31, 33, 34
To date, seven STAT proteins (STAT1–4, 5a, 5b, 6) have been cloned and characterized.52 Two isoforms of STAT1 (STAT1a and STAT1b) are produced through alternative splicing and differ at their C-termini.53 Unlike STAT1a, STAT1b lacks the transcriptional activation domain and thus functions as a signal transducer but not a transcriptional activator. Complementation of STAT-deficient mutant cells demonstrates that STAT1 is essential for IFN-α, -β, and -γ signal transduction, whereas STAT2 is required for IFN-α and -β signaling only.54, 55 The functional importance of STAT1 in IFN signaling has been further supported by the failure of STAT1-deficient mice to respond to IFNs and by the heightened susceptibility of these mice to viral and microbial infections.56, 57
Two types of regulatory DNA elements are recognized by IFN-activated STATs and control the transcription of IFN-stimulated genes. The IFN-stimulated response element (ISRE) is a highly conserved enhancer that responds to IFN-α and -β.31 Genes stimulated by IFN-γ contain a cis-acting element called the IFN-γ activated site (GAS).34 The core sequence of the ISRE is a direct repeat of GAAA spaced by one or two nucleotides: GAAAN(N)GAAA. Mutational analysis of ISRE reporter constructs defined the minimal element that is necessary and sufficient for IFN responsiveness.58 The ISRE is recognized by three DNA-binding complexes designated IFN-stimulated gene factor 1 (ISGF-1), IRF-1, and ISGF-3. Unlike ISGF-1, which is constitutively expressed, IRF-1 and ISGF-3 are induced by IFNs.59 ISGF-3 is a heterotrimeric complex of STAT1, STAT2, and p48/IRF-9.52 STAT1 and STAT2, activated via tyrosine phosphorylation, associate with p48/IRF-9, translocate to the nucleus, bind the ISRE and activate transcription.60 The GAS consensus sequence is AANNNNNTT.31 The GAS element is conserved between species and can be contained within the ISRE. IFN-γ stimulation induces tyrosine phosphorylation of STAT1a, which forms homodimers (also called “gamma activated factor” [GAF]) and binds to GAS to activate transcription.32
Phosphatases play a key role in turning off IFN signaling. Src-homology 2 domain–containing protein tyrosine phosphatase-1 (SHP-1) and SHP-2 are protein tyrosine phosphatases that contain SH2 domains.61 SHP-1 can dephosphorylate JAK family kinases and terminate signaling.62 Its negative regulatory role in IFN signaling is demonstrated by a heightened response to IFNs in SHP-1–deficient cells.63 Similarly, SHP-2–deficient cells show augmented STAT activation and reduction of cell viability in response to IFNs.64 Other protein tyrosine phosphatases also regulate JAK and STAT proteins and may down-regulate IFN signaling.43, 65, 66, 67
A family of suppressor of cytokine signaling (SOCS, also known as “CIS-cytokine-inducible SH2”) proteins has been identified.68, 69 These proteins have a central SH2 domain and a conserved C-terminal SOCS box (also known as “CIS-homology domain” or “CH domain”). Most SOCS proteins are induced by several different cytokines, and some of them have been shown to negatively regulate cytokine signaling through binding and inactivation of JAKs and STATs,70targeting the protein for degradation, or both.71 Importantly, SOCS proteins are induced by IFNs.72, 73 Stable expression of SOCS1 or SOCS3 blocks IFN-mediated antiviral effects and IFN-induced growth arrest.72, 73 Thus, these SOCS proteins may be the effectors of a negative feedback mechanism that terminates the IFN response (Fig. 32.1).
Although JAK-STAT pathways play an essential role in IFN signaling, other kinases and transcriptional factors are also involved. The antiproliferative activity of IFN-α in T cells requires components of the T-cell receptor signaling pathway, including the Lck and ZAP-70 protein tyrosine kinases.74 IRF-1 and IRF-2, transcriptional factors related to p48,75 regulate ISG expression by binding to ISREs.76, 77 IRF-1 acts as a positive regulator of IFN-α-induced, IFN-β-induced, and IFN-γ-induced genes, whereas IRF-2 represses the effects of IRF-1.78, 79 These antagonistic factors may play a role in oncogenesis. Forced expression of IRF-2 resulted in transformation and enhanced tumorigenicity of NIH3T3 cells, which was reversed by expression of IRF-1.80 Transgenic mice deficient in IRF-1 or IRF-2 confirm their important regulatory roles.81 The IFN consensus sequence-binding protein (ICSBP) is another negative regulatory factor that binds to the ISRE of many IFN-regulated genes, including the major histocompatibility complex (MHC) class I genes.82 Expression of ICSBP is restricted to cells of the hematopoietic lineage and is induced by IFN-γ but not by IFN-α and IFN-β.83 Yeast two-hybrid screens have identified the protein inhibitor of activated STATs (PIAS) gene family.84 PIASs bind to STAT1 and STAT3 dimers, thereby blocking their DNA-binding activity.
Mechanism of Interferon Resistance
Despite the successful application of IFNs to the treatment of several malignancies, the potential of the IFNs in antitumor therapies has not yet been fully realized. So far, the mechanism of IFN resistance in human cancer patients has been little studied. Although IFN-α results in an excellent hematologic response in 75% of patients with chronic myelogenous leukemia (CML), it induces complete cytogenetic remission in fewer than 20%. This suggests the presence of partial or complete primary IFN resistance in nonresponding patients.85 On the other hand, development of acquired IFN resistance in vivo appears to be common and is indicated by loss of IFN responsiveness in some patients who were initially responsive to IFNs. This is illustrated by a patient with T-cell lymphoma whose initial positive response to IFN therapy was followed by rapid progression, due to the appearance of a subpopulation of IFN-resistant malignant cells.86
Interferon Signaling Molecules in Interferon Resistance
Cell lines unresponsive to IFNs have been generated by mutagenesis, and these lack distinct IFN signaling molecules, including components of IFN receptors, JAK kinases, or STATs.32 Complementation of the mutant cell lines with the corresponding signaling molecules restores the IFN response.32 Defects of signaling molecules in human tumor cells have also been reported. An IFN-resistant human leukemia cell line lacked IFN receptor expression.87 In vivo sensitivity and resistance of CML cells to IFN-α correlated with reduced receptor binding.88 A IFN-resistant human tumor CTLL cell line (Hut78R) lacks STAT1 expression.89 IFN-α-resistance of renal carcinoma cell lines was associated with defects in STAT1 induction.90 These observations indicate that defects in the IFN receptor and STAT1 may exist in certain IFN-resistant human tumor cells and may block IFN antitumor activity. Interestingly, in contrast to the antiproliferative effect of IFN-α on the parental cells, increased concentrations of IFN-α caused a marked stimulation of growth in the IFN-resistant Hut78R cells.89 Thus, STAT defects might also be involved in tumor progression.
SHP-1 involvement in human leukemia is suggested by the localization of the SHP-1 gene at chromosome 12p13,91 a region frequently affected in acute lymphoblastic leukemia (ALL), and by the deletion of the SHP-1 gene in some ALL cases with 12p abnormalities.92 Given the negative regulatory role of SHP-1 in IFN signaling,63 ALL cases with reduced or absent SHP-1 expression could be predicted to be more sensitive to IFNs and are potential candidates for IFN therapy. Increased expression of SOCS proteins can potentially block IFN signaling.69
The biologic activity of IFNs depends on the induction of specific genes that affect cell morphology, cell viability, cell cycle progression, differentiation, and intercellular interactions. Defects in IFN-induced gene expression were detected in IFN-resistant primary leukemia cells.93 The identification of novel ISGs using the DNA-chip technique will help to further assess the involvement of ISGs in IFN resistance.94 Microarray analysis identified changes in gene expression following development of IFN resistance in cutaneous T-cell lymphoma in vitro.95 The parental IFN-sensitive line and the resultant IFN-resistant line both displayed normal STAT1 activation and ISG induction. The gene MAL was overexpressed in resistant cells and was highly expressed in tumor biopsies of patients with cutaneous T-cell lymphoma.
Besides proteins that are intrinsic components of the IFN-signaling pathways, a number of other cellular factors may also participate in IFN resistance. IFN resistance correlated with heightened expression of the bcl-2 proto-oncogene in primary myeloma cells.96 As induction of apoptosis may be important in IFN-mediated antitumor activity,97 overexpression of bcl-2 protein may protect the tumor cells from IFN- induced apoptosis and confer IFN resistance. Viruses produce factors that block IFN responses. Adenovirus, Epstein-Barr virus, and hepatitis B virus have all been implicated in the pathogenesis of human malignancies. The E1A and virus-associated (VA) I RNA of adenovirus, the EBNA-2 protein of Epstein-Barr virus, and the terminal protein of hepatitis B virus inhibit cellular responses to IFN.93, 98, 99 Therefore, IFN resistance in virus-associated human tumors may be mediated, at least in part, by the expression of specific viral proteins.
ANTITUMOR MECHANISMS: CELLULAR AND MOLECULAR
Angiogenesis is the process of new blood vessel formation from existing vessels and is a requirement for tumor growth.100 IFNs inhibit angiogenesis by altering the angiogenic potential of tumor cells as well as inhibiting the angiogenic capacity of endothelial cells. Following IFN treatment, tumor vessels undergo coagulation necrosis—a sign of disrupted blood flow.101 Inhibition of angiogenesis by IFNs precedes the antiproliferative effects on tumor cells and can be detected within 24 hours of tumor cell inoculation.102 Tumor progression studies of IFN-sensitive and IFN-resistant bladder carcinoma cell lines in mice show that systemic administration of IFN-α reduces tumor cell growth in the IFN-sensitive cells by directly regulating the expression of basic fibroblast growth factor (bFGF), an angiogenic growth factor.103 IFN-α and IFN-β both down-regulated bFGF in other human carcinoma cells, including in the prostate, colon, and breast.104 This down-regulation correlated with reduced vascularization and tumor growth.103 Knockout studies in tumor cell lines showed that STAT1 was necessary for IFN modulation of bFGF signaling.105
In addition to its action on bFGF, IFN can inhibit angiogenesis by acting on other angiogenesis mediators. IFN inhibited VEGF mRNA and protein expression in neuroendocrine tumors by regulating VEGF promoter activity.106 IL-8 is a potent mediator of angiogenesis107 and consequently tumorigenesis.108 IL-8 protein production can be inhibited by IFN-α2b109 and IFN-β.110 IL-8 is a member of the C-X-C chemokine family and contains the ELR binding motif.111 Other IFN-stimulated genes in the chemokine family that lack the ELR motif include I-TAC, Mig, and IP-10, all of which function as angiogenic inhibitors111 are also IFN-stimulated genes.94 GTPases are a family of proteins that function as molecular switches in signal transduction pathways. Several GTPase families are induced by IFNs. These include the Mx proteins (discussed later in “Direct Antitumor Mechanisms”) and the guanylate-binding proteins (GBPs). These GTPases have a distinct hydrolysis profile, since they bind GTP, GDP, and GMP with similar affinity and can hydrolyze GTP to GDP or GMP.112, 113 To date, five human GBPs (hGBP1–5) and five murine GBPs (mGBP1–5) have been identified. They are closely related and have similar tissue expression patterns during infection.114 In endothelial cells, hGBP1 functions as an inflammatory response factor that can inhibit endothelial proliferation115 and angiogenesis.116 Thus, in addition to its antiviral activity, GBP1 may have antitumor effects through inhibition of angiogenesis. The third family of GTPases includes IRG-47,117 LRG-47,118TGTP/Mg21,119, 120 and IGTP,121 all approximately 47 kd, and they may exert antiviral effects by regulating intracellular membrane trafficking.122, 123
Clinically, IFN-α2b has proven effective in the treatment of infantile hemangiomas,124 hemangioblastomas,125 and giant cell tumor of the mandible.126 Clinical efficacy in all three instances correlated with decreased bFGF protein. Kaposi's sarcoma, a neoplastic disease of endothelial origin, is the most common neoplasm in AIDS patients and responds to treatment with IFN-α2b.127 Physiologic and pathologic angiogenesis is believed to be regulated by the balance between angiogenic activators and inhibitors. The “angiogenic switch” occurs when the level of activators exceeds that of the inhibitors.128 Endogenous IFN-α/β signaling plays a role as a negative regulator, keeping the angiogenic switch in the off position. IFN-α/β receptor knockout mice have increased angiogenesis and tumorigenesis compared with wild-type mice.129
The in vivo antitumor activity of IFN may be mediated by activation of immune cells as well as enhance the immunogenicity of tumor cells. IFNs enhance the activity of cytotoxic and helper T cells,130, 131 natural killer (NK) cells,132 macrophages,133 and dendritic cells.134 IFN-γ promotes cytotoxic T cell expansion by up-regulating IL-2 gene expression.135 IFNs activate NK cells and macrophages both in vitro and in vivo.136 Furthermore, IFNs can induce expression of Apo2L/TRAIL on immune effector cell surfaces, sensitizing tumor cells to T cell–mediated and NK cell–mediated cytotoxicity.137 Treatment of both immunocompetent and athymic-nude mice with IFN-α–blocking or IFN-β–blocking antibodies enhances the growth of several different murine tumors,138suggesting a role for immune cells in IFN antitumor effects. In addition to stimulating immune effector cells, IFNs up-regulate the expression of major histocompatibility (MHC) antigens, which facilitates activation of CD8+ cytotoxic T cells.139, 140, 141, 142 IFNs not only up-regulate the transcription of MHC class I genes but also coordinately induce expression of additional proteins required for the surface expression of the mature MHC class I complex.139, 140, 143This complex contains the MHC class I polypeptide, β2-microglobulin, and an 8–to 10–amino acid antigenic peptide bound to the MHC polypeptide. As nascent class I molecules are synthesized, they associate with β2-microglobulin, also an ISG, in the endoplasmic reticulum for transport to the cell surface. The generation of antigenic peptides for loading onto class I molecules occurs in the proteasome.144 The three subunits, low molecular weight protein-2 (LMP-2), LMP-7, and MECL/LMP-10, that make up the proteasome are all ISGs.145, 146 In addition, the transporter associated with antigen processing (TAP) is induced by IFN-γ.147 TAP transports the processed peptides from cytosol to the ER for loading onto class I molecules. Two additional proteins involved in MHC class I antigen presentation, tapasin and the ER protein gp96, are induced by IFN-γ.139 IFNs also induce MHC class II proteins,139 which present peptide antigens to CD4+ T helper cells.148 The MHC class II transactivator factor (CIITA) is considered the master regulator of MHC class II expression and is induced by IFN-γ.149 In addition, three of the cathepsins, proteolytic enzymes located in the lysosome and thought to be partly responsible for peptide antigen processing and loading onto MHC class II protein,150 are also up-regulated by IFN-γ.139
IFNs induce tumor-associated antigens,151 such as carcinoma embryonic antigen152 and Tag-72,151 and Fc receptors153 on the surface of tumor cells, subjecting them to enhanced immune surveillance. IFNs induce a number of growth factors and cytokines. ISG-15, a secreted protein induced by IFN-α and IFN-β, induces IFN-γ synthesis by T cells and proliferation of NK and lymphokine-activated killer (LAK) cells.154 Chemokines are low molecular weight, secreted proteins that function as chemoattractants. IFN-induced chemokines include RANTES,155 IP-10,156 MCP-1,157 MIP-1α, MIG,158 and I-TAC.159 These proteins are chemoattractive to both lymphocytes and monocytes and play a crucial role in recruiting these cells into tissues.
Direct Antitumor Mechanisms
The pleiotropic cellular effects induced by IFNs are mediated primarily by the diverse activities of interferon-stimulated genes (ISGs). In the last few years, DNA microarrays have identified hundreds of new ISGs (Table 32.4). These oligonucleotide arrays identified genes induced by IFN-α, IFN-β, or IFN-γ 94 (http://www.lerner.ccf.org/labs/williams/der.html). Although type I and II IFNs regulate a number of unique genes, there is significant overlap in the genes regulated by both classes.94, 141
Some ISGs initially found to mediate antiviral activity were subsequently implicated in the antiproliferative and immunomodulatory effects of IFNs.160, 161 One of these proteins is the double-stranded RNA-dependent protein kinase (dsRNA-PKR). PKR is induced by type I and II IFNs, and upon activation, it slows cellular and viral proliferation by phosphorylating the eukaryotic initiation factor-2, which inhibits protein synthesis.160 PKR can also be activated in a dsRNA-independent mechanism by the protein PACT.162 In the absence of viral infection, PKR can induce or enhance apoptosis but also may be required for normal cell proliferation. PKR enhances Apo2L/TRAIL-induced apoptosis by preventing protein synthesis following Apo2L/TRAIL binding to its receptor.160
The family of 2′-5′-oligoadenylate synthetases (2-5 synthetase) exert antiviral activity.163 Following activation by dsRNA, these enzymes polymerize ATP into 2′-5′-oligoadenylates. These 2′-5′-oligoadenylates in turn activate the enzyme RNaseL. RNaseL inhibits protein synthesis by degrading single-stranded RNA. Recently, this gene was found to be a strong candidate for the hereditary prostate cancer allele.164 RNaseL induces apoptosis in prostate carcinoma cells treated with 2′-5′-oligoadenylate analogs; mutations in the RNaseL gene prevent apoptosis.165
The best characterized GTPases are the Mx proteins, MxA and MxB, which belong to the dynamin superfamily of large GTPases.141, 166, 167 Mx proteins are induced by type I but not type II IFNs. MxA has antiviral activity against negative-strand RNA viruses, including the influenza virus.166 Animal studies have shown that MxA is sufficient to block viral replication in the absence of IFN.167 Genetic studies indicate that MxA has antiviral activity against many RNA viruses, but to date MxB has not been shown to exert any antiviral activity.141 IFN-γ–mediated microbial and tumor cell killing is mediated by nitric oxide (NO). NO and its reactive intermediates activate both neutrophils and macrophages and have been included here because their products can enhance tumor cell killing. The NO synthetase (NOS) family of enzymes catalyze NAPDH-dependent oxidation of arginine to yield NO. One of these family members, inducible NOS (iNOS), is induced by IFN-γ.141 IFN-induced iNOS can suppress tumor formation as well as metastasis by regulating genes related to survival, metastasis, and angiogenesis.154
The interferon p200 family of proteins, induced by both type I and II IFNs, play a role in cellular growth regulation and differentiation. The p200 family of proteins contain a unique 200-amino acid domain and include six murine members (p202a, p202b, p202c, p203, p204, and p205) and three human members (IFI-16, myeloid cell nuclear differentiation antigen [MNDA], and absent in melanoma 2 [AIM2]).168 IFI-16, AIM2, and p202 inhibit cell proliferation.168 The murine p202a gene inhibits proliferation by binding the tumor suppressor gene RB,169 p53,170 and the transcription factor E2F.171, 172 This inhibition of proliferation results in loss of the transformed phenotype173 and decreased tumor formation in mouse models.174
TABLE 32.4 INTERFERON (IFN)-REGULATED GENE PRODUCTS AND FUNCTIONS
TABLE 32.5 PHARMACOKINETICS OF INTERFERONS
Nuclear bodies (NBs) are multiprotein complexes in the nucleus that are associated with human diseases, including acute promyelocytic leukemia, AIDS, and viral infections.175 The promyelocytic (PML) protein, the NB organizer protein,176 is also an ISG. Studies in PML knockout mice indicate that PML is necessary for apoptosis.177 Other proteins that make up NBs (sp100, sp140, sp110, and ISG-20) are also ISGs. Thus, proteins that make up NBs may play a role in the IFN response to cancer, apoptosis, and immunomodulation.176
TABLE 32.6 INTERFERON SIDE EFFECTS
IFN-α decreased the activities of cyclins and cyclin-dependent kinases (CDKs) by induction of CDK inhibitors p21WAF1 and p15, with associated prevention of retinoblastoma protein (Rb) hyperphosphorylation, thus keeping this tumor suppressor in the active state. Activated Rb binds and inactivates transcription factors like E2F that are required for cell cycle progression. 178, 179, 180, 181, 182 Induction of the CDK inhibitor p21WAF1 by IFN-α in Daudi Burkitt's lymphoma cells leads to cell cycle arrest, differentiation, and apoptosis.178
Unlike apoptosis induced by camptothecin, programmed cell death in response to IFNs is a late effect, requiring 48 hours of exposure. Underlying this latency is the requirement for gene induction. Gene array experiments have identified apoptosis-promoting ISGs.183 In CML184 and multiple myeloma cells,185induction of the death receptor Fas/CD95 by IFN-α resulted in apoptosis through recruitment of FADD (Fas associated death domain) and subsequent activation of caspase-8/FLICE. Intralesional administration of IFN-α into basal cell carcinomas increased Fas expression and led to regression.186 Cholangiocarcinoma cells were sensitized to Fas-mediated apoptosis by pretreatment with IFN-γ.187 Similarly, IFN-γincreased susceptibility of melanoma cells to apoptosis by Fas activators.188 IFN-β induced Apo2L/TRAIL (TNF-related apoptosis-inducing ligand) in melanoma cells more potently than did IFN-α.189 In myeloma cells, IFN-α induced Apo2L/TRAIL expression; apoptosis was inhibited by expression of the dominant negative mutant death receptor 5 (DR5Δ), which binds Apo2L/TRAIL without eliciting intracellular signals.190 Promoter mapping, RNA interference, and ChIP studies suggested that Apo2L/TRAIL induction in breast cancer cells by IFN and retinoic acid (RA) is mediated through IRF-1 activation of the Apo2L/TRAIL promoter.191 Combination treatment with IFN and RA synergistically induced Apo2L/TRAIL, which may explain synergistic anticancer effects.191 Induced by IFN-β in melanoma cells,192 XAF-1 promotes apoptosis by interfering with the apoptosis inhibitor XIAP,193 thus preventing inactivation of caspase-3, -7, and -9.194 XAF-1 overexpression in A375 melanoma cells by itself did not result in apoptosis but sensitized cells to Apo2L/TRAIL-induced apoptosis.192
Caspases are key apoptotic enzymes that are activated by either external signals via death receptors or internal stresses via mitochondria. In the final common pathway, activation of caspase-3 brings about ordered breakdown of the cell.195, 196, 197 IFN-γ sensitized breast cancer cells to death receptor–mediated apoptosis, associated with up-regulation of caspase-8 expression and IRF-1 induction.198, 199 In astrocytoma cells, IFN-γ increased expression of caspase-1, -4, and -7,200 whereas caspases-3, -4, -7, and -8 were increased in colon cancer cells.201 Type I IFNs induced caspase-4 in melanoma161 and fibrosarcoma cells.202
Mice lacking IRF-8 develop a disease similar to CML. Interestingly, overexpression of IRF-8 in Bcr-Abl–transformed cells inhibited leukemogenesis as well as resistance to chemotherapy with imatinib, which correlated with reduced bcl-2 expression.203 IRF 5, inducible by both p53 and type I IFNs, was recently described to have a p53-independent tumor suppressor function in lymphoma cells.204
Inositol hexakisphosphate kinase2 (IHPK2) was identified as a regulator of IFN-induced death in ovarian cancer cells by an antisense technical knockout approach.205 It is located on chromosome 3p21, a region frequently affected by loss of heterozygosity and chromosomal rearrangements in human cancer. Overexpression of IHPK2 sensitized tumor cell lines to apoptosis in response to a variety of chemotherapeutics and ionizing radiation, suggesting a role in a central apoptotic pathway.206
Inducible by IFN-α, SCF, G-CSF, and EGF, phospholipid scramblase 1 (PLSCR1) localizes to the plasma membrane207, 208, 209, 210, 211 but can translocate to the nucleus via nuclear membrane receptors.207 It may play a role in trans-bilayer movement of phospholipids during apoptosis, thereby providing macrophages with a signal for engulfment.212, 213, 214 Ovarian cancer cells overexpressing PLSCR1 grew slower in nude mice compared to vector-transfected cells, and the resultant tumors were infiltrated by neutrophils and macrophages.215 Thus, by inducing PLSCR 1, IFNs might facilitate tumor cell phagocytosis by macrophages.
Identified as mediators of IFN-γ–induced apoptosis, gene,216 death-associated protein kinases (DAPK) are serine threonine kinases with ankyrin and death domains that induce caspase-independent cell death.217 Reduced expression correlated with malignant behavior while restoration of expression led to apoptosis of mouse lung tumors.218 Their expression is frequently silenced in human malignancies, especially in lymphoid tumors,219 further supporting their role as tumor suppressors. DAPK7, also called ZIP kinase, phosphorylated MDM2 and p21WAF1, with resultant prolongation of the p21WAF1 half-life, providing a DAPK–mediated link between the p53 and IFN pathways.220
In summary, IFNs increase expression of a number of cell cycle inhibitory and apoptotic genes. These direct effects on tumor cells likely contribute to the anticancer effect in vivo. In some instances, addition of another drug is required for full activation of apoptotic pathways, providing a rationale for combination trials. Combination of IFNs with inhibitors of survival genes, like epidermal growth factor receptor,221, 222 may prove beneficial.
Clinical Pharmacology of Interferons
IFNs can be measured in serum using bioassays, which measure protection from viral cytopathic effect, or with more direct immunological tests. Both methods have sensitivities around 5 U/mL, while reproducibility may be higher for the latter. Most studies used bioassays and generally confirmed higher maximum serum levels of IFN-α compared to IFN-β or -γ after subcutaneous administration (Table 32.5). Additionally, a number of biological effects that result from gene induction by IFNs (e.g., neopterin or β2-microglobulin serum levels, mononuclear cell 2-5 A synthetase production, and NK cell activation) have been measured both to document in vivo activity and in an attempt to predict response. Unfortunately, the latter aim has not been achieved, but 2-5 A synthetase has correlated to IFN dose and serum level in some studies,223 which may explain why some studies suggested a correlation between 2-5 A levels and response.
When given subcutaneously or intramuscularly to humans, approximately 80% of IFN-α is absorbed.223 While local effects of oral IFN-α seem possible in Sjogren's disease224, 225 and measles,226 the promising antimelanoma effect observed in mice227 could not be demonstrated in limited clinical evaluation for human cancer.228 After intramuscular or subcutaneous administration of IFN-α, the serum or plasma levels peak at 1 to 8 hours, and IFN-α remains detectable for at least 4 to 24 hours. Clearance varies between 4.8 to 48 L/hour, and the terminal elimination half-life is 4 to 16 hours.223 The Kirkwood schedule of high-dose IFN-α2b therapy for melanoma (20 million IU/m2 intravenously per day 5 days a week for 4 weeks, followed by 10 million IU/m2 subcutaneously three times a week)229 may yield peak serum levels of 2,500 IU/mL at the end of the intravenous phase and 150 IU/mL after subcutaneous administration.223, 230
IFN-α2 has been chemically modified in order to increase its serum half-life. A monopegylated IFN-α2b has been developed by Schering Plough (Kenilworth, NJ). It has reduced renal clearance and retains approximately 27% of the in vitro antiviral activity of native IFN-α2b. Hoffmann-La Roche (Nutley, NJ) similarly has developed a monopegylated species of IFN-α2a. This species has a 70-fold increase in serum half-life compared with native IFN-α2a.231 Linkage of a 40-kd branched polyethylene glycol (PEG) molecule to IFN-α2a or a 12-kd linear PEG moiety to IFN-α2b markedly altered the pharmacokinetic profile and increased activity against hepatitis C in a direct clinical comparison of once weekly subcutaneous PEG-IFN with the parent compound given subcutaneously. three times a week.232 The larger PEG moiety of PEG–IFN-α2a leads to the slowest absorption half-life and the longest elimination half-life (Table 32.7).233
PEG-IFN-α2b at 1µg/kg per week induced a biological response (increase in serum neopterin and mononuclear cell 2-5 A synthetase activity) similar to that of IFN-α2b at 3 million IU administered subcutaneously three times a week.234 The efficacy of PEG–IFN-α2b has been clinically studied in patients with chronic myelogenous leukemia (CML) and those with advanced solid organ malignancies, particularly melanoma and renal cell carcinoma. A phase I dose-escalation trial of PEG–IFN-α2b administered once weekly was conducted in 27 patients with chronic phase CML who had been previously treated with native IFN α2b.235Thirteen of the patients (48%) achieved a complete hematologic or improved cytogenetic response.
Accumulation of serum levels of PEG–IFN-α2b was observed in several dose cohorts at week 4. No dose-limiting toxicities were observed in any of the cohorts through the 4-week study period, but they did occur in those patients treated with higher doses on an extended study protocol.235 After encouraging results for PEG–IFN-α2b in CML patients who had failed IFN-α treatment,236 it was directly compared with the parent drug as initial treatment for chronic phase CML in a phase III study, where it showed efficacy and toxicity at 6 µg/kg per week similar to those of IFN-α2b at 5 million IU/m2 per day.237 Anticancer activity against solid tumors was demonstrated in a phase I/II trial of PEG–IFN-α2b, which determined 6 µg/kg per week as the maximal tolerated dose (MTD) and showed evidence of drug accumulation with an area under the curve (AUC) of 374 pg/hour per mL for week 1, compared with 480 pg/hour per mL at week 4 for patients treated with the MTD.238 In a phase II study of pegylated IFN-α2a given subcutaneously at 450 µg once a week to patients with advanced renal cancer, peak levels in the first week (mean 19 ng/mL) were reached 48 hours after the first injection and were maintained for the remainder of week 1. Over the following 5 to 9 weeks, a rise to a plateau (54 ng/mL) was observed. Toxicity and efficacy were comparable to historical controls treated with the parental compound.239 A small randomized trial of PEG–IFN-α2b given at 1 µg/kg once or twice a week showed improved pharmacokinetics and viral kinetics with twice a week dosing.240 Whether PEG–IFN-α will increase antitumor activity must be addressed in future studies. Additionally, other members of the IFN-α family, such as IFN-α1, which is currently undergoing clinical evaluation, may provide the same clinical benefits with fewer side effects.241
TABLE 32.7 PHARMACOKINETICS OF PEGYLATED PARENTAL IFN-ALPHAS
A single species in humans, IFN-β exists as a 23-kd glycoprotein containing 166 amino acids, with an isoelectric point between 6.8 and 7.8, and an N-linked glycosylation site at asn80. Animal studies suggest IFN-β is metabolized primarily in the liver.223 After intravenous injection, the terminal elimination half-life is about 1 to 2 hours, and IFN-β remains measurable for up to 4 hours (Table 32.5). In contrast, after a single subcutaneous or intramuscular injection, serum IFN-β is barely detectable.223 However, intravenous and subcutaneous administration of the same dose elicited similar pharmacodynamic responses, including 2-5 A synthetase induction.242 Oral IFN-β1a had no effect on disease or neopterin levels in multiple sclerosis patients, suggesting proteolysis in the intestinal tract.243 While in vitro and animal data suggest greater antitumor activity of IFN-β compared with IFN-α,189, 244, 245 there have only been a limited number of clinical trials utilizing IFN-β. IFN-β intravenous dosing 2 or 4 times per week resulted in clinical responses in 5 out of 25 patients with advanced malignancies in phase I and I/II trials.246, 247 In a phase I trial of IFN-β1a given to patients with malignancies unresponsive to standard therapy, 2-5 A synthetase levels remained elevated throughout the 28-day subcutaneous dosing phase; there was no correlation of serum level with IFN dose (1.5 to 24 million IU/m2). Out of 29 patients, 5 had stabilization of disease.248
Three avenues of improving IFN-β pharmacokinetics are being pursued and have generated encouraging preclinical data. Albuferon is a recombinant protein resulting from fusion of the IFN-β peptide with albumin. In monkeys, the bioavailability of subcutaneous Albuferon was 87%, plasma clearance was reduced by 140-fold, and the terminal half-life increased 5-fold, while in vitro and in vivo activity was preserved.249 Fusion of IFN-β to soluble recombinant type I IFN receptor subunit (sIFNAR-2) prolonged the half-life and increased antitumor activity in mice.250 Finally, pegylation of IFN-β1a with a linear 20-kd molecule increased the maximum serum concentration achieved 4-fold, while the AUC increased 10-fold and the half-life increased 3-fold.251
After subcutaneous or intramuscular administration, 30 to 70% of IFN-γ is absorbed, and the terminal elimination half-life is 25 to 35 minutes; after intravenous injection, IFN-γ remains detectable in serum up to 4 hours (Table 32.5). Like IFN-β, IFN-γ appears to be metabolized primarily by the liver.223 A phase I trial in colon cancer patients achieved IFN-γ concentrations greater than 5 U/mL for more than 6.5 hours following 100 µg/m2 given subcutaneously.252 Pegylation increased the half-life of PEG–IFN-γ in rats, and activity was preserved,253 but this molecule has not yet been evaluated in patients.
IFN Fusion Molecules
Gene constructs have made possible protein fusion molecules. Albuferon is a novel hybrid protein produced by the genetic fusion of human serum albumin and a recombinant IFN-α to form a single polypeptide molecule.241, 254 In vitro studies suggest comparable and in some cases improved antiproliferative activity compared with native IFN-α2b.241 Studies in primates demonstrate a markedly longer circulating half-life than that of IFN-α2b. This increase in half-life correlates with significant and prolonged increases in mRNA transcripts of oligoadenylate synthase, a known IFN-stimulated gene product.254
Recombinant technology allows the production of sequence-altered IFNs.255 In vitro studies of several gene-shuffled IFN products show promising results and may lead to translational studies of IFNs with improved efficacy and reduced side effects.241
IFNs cause several consistent acute and chronic side effects influenced by dose, route, and schedule.256, 257 The acute side effects are mainly constitutional. Nearly all patients experience fever, chills, malaise, myalgias, arthralgias, and headache beginning 2 to 3 hours after the first dose and lasting approximately 6 to 8 hours (Table 32.6). Fever and chills can be attenuated with the use of acetaminophen and narcotics, respectively. Nausea and vomiting may occur as part of the acute side effects, but they are infrequent.258 Tachyphylaxis to the acute side effects develops quickly with subsequent doses. However, the symptoms may recur if treatment is interrupted even for a few days.259
Elevation of hepatocellular enzymes may occur acutely but is usually mild and reversible. Dose modifications, however, are recommended with significant increases of hepatocellular enzymes, since fatal hepatotoxicity has occurred in rare instances.260 Serious hepatocellular injury may occur in those patients with preexisting liver disease.260 Changes in serum lipids consisting of an increase in triglycerides with or without a decrease in total cholesterol may be observed in some patients. Marked hypertriglyceridemia may respond to treatment with gemfibrozil.261
Acute hematologic toxicity is often observed.258 The hematologic effects most commonly observed are neutropenia and thrombocytopenia. Neutropenia is rapidly reversible because it results not from maturation arrest of granulocyte precursors but from impaired release of granulocytes from the bone marrow. No increase in infectious complications has occurred during IFN-induced neutropenia.
The chronic side effects of fatigue, weight loss, and mood alteration can be difficult to control and are the main reasons for discontinuation of IFN-α2b therapy.260 Dosing delays or dose reductions due to toxicity during maintenance treatment with IFN-α2b were required in 36 to 52% of patients enrolled in the three intergroup trials that evaluated adjuvant high-dose IFN for high-risk melanoma.258 These chronic effects are generally not observed with the administration of IFN-β.
Fatigue and anorexia are the dose-limiting toxicities with chronic administration of IFN-α.262 The mechanisms are poorly understood, but weight loss may be significant (greater than 10%) with the use of IFN-α263, 264 Both weight loss and fatigue are uncommon with chronic administration of IFN-β265, 266 Therapy with high-dose IFN-α may lead to a syndrome of altered mood, memory impairment, and cognitive slowing.267 Depressed mood and occasionally symptoms of major clinical depression may prevail and are the most commonly identified neuropsychiatric toxicity in patients receiving IFN-α2b.258 Although the mechanisms of IFN-induced mood changes are poorly understood, recent data demonstrate significant increases in serum tryptophan degradation products and neopterin concentrations in patients who were receiving IFN-α and developed depression when compared with those patients who were receiving IFN-α but did not develop depression.268 Patients with a history of a mood disorder or depression may still be considered candidates for treatment with IFN-α if necessary, but they may be at higher risk for developing depression while being treated.267 A recent clinical trial suggested that the use of paroxetine can prevent depression and the early discontinuation of IFN-α2b in patients receiving adjuvant therapy for high-risk melanoma.269
Changes in creatinine levels are not reported with the use of IFNs. However, mild proteinuria is commonly described, with nephrotic syndrome and acute renal insufficiency being rarely reported.270, 271 Occasional patients have developed alterations in thyroid function, but no residual toxicities in parenchymal organ function have been identified.259, 272
IFNs have activity for both hematologic malignancies and solid tumors. In CML, IFN-α2 has demonstrated sustained clinical and cytogenetic responses.273 The median survival for responding patients who show some, although not complete, evidence of cytogenetic response is approximately 6 years. More than 90% of cytogenetic complete responders will be in remission at 10 years.274 Addition of cytosine arabinoside to IFN-α2 has resulted in a further increase in major cytogenetic responses and further prolongation of survival.275, 276 Emerging resistance to imatinib has resulted in initiation of combination trials, supported by preclinical evidence of synergistic interaction. For B-cell neoplasms, the significant single-agent activity of IFN-α2 can be integrated with effective chemotherapy for low-grade and intermediate-grade non-Hodgkin's lymphoma,277, 278 with prolonged disease-free survival and overall survival. For myeloma, some, but not all, phase II and III studies have suggested that, for induction or maintenance, IFN-α2 may add to effectiveness.279, 280, 281 Prolongation of disease-free survival has emerged from use of IFN-α2 as an adjuvant to surgery for high-risk patients with primary melanoma and metastatic renal cell carcinoma.282, 283, 284, 285
Clinical trials have thus defined therapeutic effectiveness in hematologic malignancies and solid tumors. Therapeutic applications will likely broaden in the next decade (Table 32.8). A combination of biochemical and genetic approaches has led to the identification of a new cellular signal transduction pathway and more than 300 IFN-stimulated genes. Further exploration of signal transduction and the genes induced should enhance the understanding of the biologic and pharmacologic effects of IFNs, the focus of this chapter. In the next decade, the clinical benefits of this potent and pleiotropic family of cytokines for the treatment of malignancy will be even more completely realized.
TABLE 32.8 INTERFERON SYSTEM: CHALLENGES IN 2005–2015
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The authors would like to acknowledge the support of the National Institutes of Health and the National Cancer Institute (CA095020 to DJL; CA89344 and CA90914 to ECB)