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Immunocytokines (IC) are fusion proteins that use genetic linkage to fuse cytokines with immunologically reactive monoclonal antibodies (mAb) or components thereof. The goal is to retain the functions of both the cytokine and the antibody components in a single bifunctional molecule. As such, the functions of the antibody (long circulating half life, antigen specific binding, complement activation, interaction with Fc Receptors (FcRs) to induce antibody dependent cytotoxicity [ADCC]) are retained. In addition, the functions of the cytokine that are linked to the antibody (such as IL-2, IL-12, or IL-7), are also retained. The goal is to allow the biologic activities of one component of the IC (the antibody) to be expanded by colocalizing it with the biologic function of the other component of the IC (the cytokine). A few distinct immunocytokines have been created by EMD-Lexigen , and by others . These have used antibodies with some degree of selectivity for molecules expressed predominantly by tumors, and have been linked to different cytokines. The first IC to be described resulted from linking IL-2 to the 14.18 mAb that recognizes the GD2 disialoganglioside. Testing of this agent, and its derivatives, has moved forward in parallel with preclinical and clinical testing of other ICs (including the huKS-IL-2 IC that recognizes the epithelial cell adhesion molecule, which is overexpressed on many epithelial carcinomas).The purpose of this chapter is to summarize the preclinical testing of ICs, and a recently completed Phase I study, with an emphasis on recent data with the hul4.18-IL-2 IC. We also present a brief summary of preclinical data utilizing newer ICs being developed for future clinical testing.

Since the late 1980s, tumor immunology has made truly revolutionary progress. Perhaps the two most significant contributing factors are the discovery of tumor antigens (TAs) and advances in cytokine-biotechnology. Molecular characterization of T-cell-epitopes within TAs led an evolution of tumor immunology from the rather empirical observation of tumor regressions into a sophisticated science established on a solid molecular basis . In addition, the availability of recombinant cytokines and their cDNAs promoted our understanding of the role of cytokines in tumor immunosurveillance, and allowed us to examine the administration of cytokines to facilitate anti-tumor inflammatory response within the tumor microenvironment.

Much has been written regarding the use of pro-inflammatory cytokines in the treatment of cancer. This stems from their potential in the acute situation to induce death of diseased cells, as well as to destroy tumor blood vessels and activation of proteins involved in apoptosis. However, as discussed earlier, it is important to consider that several chronic inflammatory conditions lead to the development of the malignant phenotype. Examples include ulcerative colitis/Crohn disease, associated with colorectal carcinoma; Barrett’s esophagus with esophageal cancer; schistosomiasis with bladder cancer; and with gastric carcinoma/lymphoma. Stimulation of fibroblastic and tumor stroma growth, as well as induction of angiogenic and anti apoptotic factors have all been reported in the presence of chronic inflammation . In addition, secretion of a pro-inflammatory chemokine, macrophage migration inhibitory factor (MIF) has been reported to result in suppression of p53 function . This chapter will discuss the rationale for inhibiting pro-inflammatory cytokines and their potential use to treat cancer and its sequelae. Given the availability of agents to block TNF and IL-1, these proteins will be discussed in detail.

The last 15 years have witnessed a transformation in our ability to manage the debilitating symptoms associated with cancer and its treatment and thereby to optimize functional status and the quality of patients’ lives while providing the best possible anticancer therapy. Like a proactive, patient-centered approach to the effective treatment of pain, the development of highly efficacious anti-emetic regimens and the introduction of bisphosphonates for hypercalcemia and the prevention of skeletal events in patients with lytic bone metastases, the advent of biotechnology provided us with therapeutic proteins that have decreased infection and transfusion risk. The latter have dramatically improved hematopoietic cell support for patients undergoing myeloablative chemotherapy, and improved energy levels in patients suffering the frequent and debilitating fatigue associated with cancer and its treatment. The landscape of oncology practice today differs radically from that just 20 years ago with these advances in supportive care allowing patients to spend more of their time outside hospital engaged in meaningful activity. This chapter will review the role of therapy with cloned human glycoprotein ligands with hematopoietic activity in the modern supportive care of cancer patients.