Excerpt from Immunotherapeutic Targeting

Synonyms, Key Words, and Related Terms: oncology, immunology, Coley toxins, radiotherapy, innate immunity, adaptive immunity, muramyl tripeptide phosphatidylethanolamine, MTP-PE, liposomal muramyl tripeptide phosphatidylethanolamine, L-MTP-PE, tumor necrosis factor, TNF, natural killer cell, NK cell, granulocyte-macrophage colony-stimulating factor, GM-CSF, bone marrow transplantation, BMT, histocompatibility leukocyte antigen, HLA, HLA antigen, graft versus host disease, GVHD, donor leukocyte infusions, DLI, chronic myelogenous leukemia, CML, acute myeloid leukemia, AML, acute lymphoblastic leukemia, ALL, graft versus leukemia effect, GVL effect, major histocompatibility complex, MHC, monoclonal antibodies, MAB; human antimouse antibodies, HAMA, antibody-dependent cell-mediated cytotoxicity, ADCC

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Over the past 40 years, steady progress has been made in the field of pediatric oncology. This has resulted largely from the stepwise integration of multimodality therapies (chemotherapy, surgery, radiation therapy) into carefully designed complex treatment regimens tested sequentially in multicenter randomized trials. The identification of chemotherapeutic agents that can eradicate micrometastases has been the backbone of this success; however, over the past decade, an understanding of the limitations of chemotherapy has grown.

First, clinical and experimental evidence have shown that it is not uncommon for tumors to develop chemoresistance to multiple drugs concomitantly, resulting in cross-resistance to agents that may not have been received by the patient previously and that may show good activity when used in patients in whom cancer is newly diagnosed (Kaye, 1998).

Second, although many pediatric tumors show better clinical response to intermediate-dose intensities than to low-dose intensities (Smith, 1991), response appears to plateau at high doses, thus limiting the effectiveness of continued chemotherapy dose escalation (Smith, 1996).

Finally, although several new cytotoxic agents that are active against adult carcinomas (eg, taxanes) have been developed over the last decade (Choy, 2001), these new chemotherapy agents have limited efficacy in a wide variety of tumor types. The need is growing for the development of effective alternative anticancer therapies for use in children with tumors.

The 1990s were marked by dramatic progress in the understanding of the basic biology of both cancer and tumor immunologies. Evidence currently suggests that the mechanisms responsible for resistance to cytotoxic agents generally do not confer resistance to immune-mediated mechanisms of tumor cell killing (Cullen, 2001; Shtil, 2000; Kleinerman, 1995; Giavazzi, 1984; Kontny, 1998). Immunotherapy can be divided broadly into the categories of innate immunity stimulation, T-cell–based therapy, and monoclonal antibody (MAB)–based therapy. This article begins with a brief review of the historical background of immunotherapy for cancer, then addresses the central scientific principles that serve as the basis for the development of immunotherapies and reviews clinical experience in pediatric oncology using each approach