The role of alpha interferon in the biomodulation of disease: Preface

The treatment of most solid tumors remains unsatisfactory. For patients with advanced disease, combination chemotherapy may offer transient palliation, but improvement in overall survival is uncommon. In the area of hematologic malignancies, which are generally more sensitive to chemotherapy, the majority of patients still fail with uncontrolled systemic disease. Biological agents are potentially useful in the treatment of advanced disease, and offer certain advantages as compared with chemotherapy. For example, they may have greater antitumor specificity because of their ability to recruit immunologically active effector cells. Furthermore, they generally have a different spectrum of toxicities from chemotherapeutic agents, so they can be used more effectively in combination therapy. The interferons (IFNs), a family of polypeptides originally identified for their antiviral activity, are a family of biologic agents that are of great interest as anticancer drugs. They demonstrate reproducible antiproliferative effects in vitro [1,2]. They are capable of augmenting multiple immune parameters including natural killer cell activity and antibody-dependent cell-mediated immunity [3,4]. In addition, shortly after their introduction into clinical trials, IFNs were found to induce remissions in tumors generally refractory to chemotherapy, such as melanoma and renal cell carcinoma, and to induce durable, complete remissions in an uncommon variant of chronic lymphocytic leukaemia, hairy cell leukaemia [5-7]. Despite these initial promising results, however, single agent IFNs have failed to exhibit significant antitumor activity against the majority of solid tumors. Shortly after their introduction into clinical trials, interest arose in incorporating IFNs with chemotherapy regimens, as early preclinical studies demonstrated therapeutic synergism for combinations of IFNs and cytotoxic agents [8-10]. In some instances these effects were dramatic; however, these studies also revealed that: (a) IFNs were capable of enhancing the effect of cytotoxic drugs independent of immune stimulation, for example, in in vitro systems or against human tumors explanted to immunoincompetent mice; and (b) the sequence of administration was less important than the drugs with which the IFNs were combined. These early studies, while providing only incomplete guidance for the transition to clinical trials, nevertheless formed the foundation for phase I trials of IFNs and the broadly-active chemotherapeutic agents such as doxorubicin, cyclophosphamide and cisplatin, as well as for drugs for which a specific biochemical interaction with IFN was identified, such as DFMO. While there are substantial preclinical data regarding the interaction of IFNs and cytotoxic agents, much of these data present difficulties in interpretation, thus making translation to the clinical setting difficult. Nevertheless, several recent clinical trials of combination therapy have demonstrated therapeutically successful results, suggesting that these different classes of agents can be combined in the clinic. Regimens combining cytotoxic drugs and IFNs are being tested with greater frequency. Most of these regimens are empirical in design, without regard to IFN/cytotoxic drug interactions. In many regimens, IFNs are combined with cytotoxic drugs with a specific rationale: biochemical modulation, combined chemoand immunotherapy; or host protection. Each is valid; however, the complexity of potential interactions requires close consideration. In order to analyse the currently available data on interactions of chemotherapeutic agents with interferons and partially resolve some of these complex issues, a symposium, "The role of alpha interferon in the biomodulation of disease," was