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INTRODUCTION

A Note on Treatment Regimens

Cancer treatment regimens change to reflect continuous advances in basic and clinical science: new drugs, both small molecules and biologicals; improved methods of targeting and timing of drug delivery; agents with altered pharmacokinetic properties and selectivities; the use of rational multidrug combinations; and greater knowledge of the basic cell biology of tumorigenesis, metastasis, and immune function, among other advances. As a consequence, this chapter presents only a few detailed treatment regimens; rather, we refer the reader to the web-based resources of the U.S. FDA (drugs@fda) and the NCCN (National Comprehensive Cancer Network). Table 71–1 provides two examples of therapeutic regimens that illustrate the complexity of current cancer drug therapy.

Development of targeted therapies for treating patients with cancer relies on the continuing process of discovery of molecular changes that drive malignant progression of human cancers. A growing number of drugs are being developed to block oncogenic pathways that lead to dysregulated cancer cell growth and survival. Targeted therapy may be combined with classical cytotoxic cancer drugs described in Chapter 70 for improved efficacy. Growth factor receptors and downstream signaling molecules are among the most actively explored targets for cancer drug discovery. The drivers of cancer growth are oncogenic pathways in malignant cells themselves (e.g., mutant or overexpressed receptors), the reaction of the tumor microenvironment (e.g., angiogenesis), and the escape of malignant cells from the host’s immune surveillance (Hanahan and Weinberg, 2011). Chapter 71 describes small-molecule drugs used in targeting pathways altered in cancer. The discussion of drugs in this chapter focuses on large molecules and cell-based therapeutics of cancer and is organized into sections:

  1. Inhibiting growth factors receptors in cancer cells

  2. Inhibiting tumor angiogenesis

  3. Activating immune cells

  4. Targeting cancer cell surface molecules to engage immune cells

  5. Cytotoxin conjugates with antibodies or cytokines

  6. Cellular therapy and vaccines

  7. Other proteins

The proteins discussed here target oncogenic pathways that contribute to cancer growth and metastatic spread as well as immune evasion and for the most part consist of monoclonal antibodies or their derivatives that recognize cell surface proteins on cancer cells or on host cells or antigens shed from cancer cells (see box Antibodies as Cancer Drugs).

Antibodies as Cancer Drugs

The general concept of harnessing the immune system to treat cancer originated with William B. Coley, a professor of clinical surgery at Cornell University. He suggested that natural immunity becomes lowered during malignancy and thus thought to raise the immune reaction by injecting bacterial toxins into sarcoma (Coley, 1910) with some successes, although also with serious adverse events. The foundation for contemporary antibody-based drugs was laid by Köhler and Milstein who, in 1975, generated the first hybridoma cell lines capable of producing monoclonal antibodies. Georges Köhler, César Milstein, and Niels Jerne shared the 1984 Nobel Prize in Physiology/Medicine “for theories concerning the specificity in development and control of the immune system ...

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