Chapter 081. Principles of Cancer Treatment (Part 25)

Antibodies In general, antibodies are not very effective at killing cancer cells. Because the tumor seems to influence the host toward making antibodies rather than generating cellular immunity, it is inferred that antibodies are easier for the tumor to fend off. Many patients can be shown to have serum antibodies directed at their tumors, but these do not appear to influence disease progression. However, the ability to grow very large quantities of high-affinity antibody directed at a tumor by the hybridoma technique has led to the application of antibodies to the treatment of cancer.Clinical antitumor efficacy has been obtained...
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Chapter 081. Principles of Cancer Treatment (Part 25) Chapter 081. Principles of Cancer Treatment (Part 25) Antibodies In general, antibodies are not very effective at killing cancer cells. Becausethe tumor seems to influence the host toward making antibodies rather thangenerating cellular immunity, it is inferred that antibodies are easier for the tumorto fend off. Many patients can be shown to have serum antibodies directed at theirtumors, but these do not appear to influence disease progression. However, theability to grow very large quantities of high-affinity antibody directed at a tumorby the hybridoma technique has led to the application of antibodies to thetreatment of cancer. Clinical antitumor efficacy has been obtained using antibodies where theantigen-combining regions are grafted onto human immunoglobulin gene products(chimerized or humanized), or derive de novo from mice bearing humanimmunoglobulin gene loci. Such humanized antibodies against the CD20 moleculeexpressed on B cell lymphomas (rituximab) and against the HER-2/neu receptoroverexpressed on epithelial cancers, especially breast cancer (trastuzumab), havebecome reliable tools in the oncologists armamentarium. Each used alone cancause tumor regression (rituximab more than trastuzumab), and both appear topotentiate the effects of combination chemotherapy given just after antibodyadministration. Antibodies to CD52 are active in chronic lymphoid leukemia andT cell malignancies. EGF-R–directed antibodies (such as cetuximab andpanitumomab) have activity in colorectal cancer refractory to chemotherapy,particularly when utilized to augment the activity of an additional chemotherapyprogram, and in the primary treatment of head and neck cancers treated withradiation therapy. The mechanism of action is unclear. Direct effects on the tumormay mediate an antiproliferative effect as well as stimulate the participation ofhost mechanisms involving immune cell or complement-mediated response totumor cell–bound antibody. Alternatively, the antibody may alter the release ofparacrine factors promoting tumor cell survival. The anti-VEGF antibody bevacizumab shows little evidence of antitumoreffect when used alone, but when combined with chemotherapeutic agents itimproves the magnitude of tumor shrinkage and time to disease progression incolorectal, lung, and breast cancer. The mechanism for the effect is unclear andmay relate to the capacity of the antibody to alter delivery and tumor uptake of theactive chemotherapeutic agent. Side effects include infusion–related hypersensitivity reactions, usuallylimited to the first infusion, which can be managed with glucocorticoid and/orantihistamine prophylaxis. In addition, distinct syndromes have emerged withdifferent antibodies. Anti-EGF-R antibodies produce an acneiform rash that poorlyresponds to steroid cream treatment. Trastuzumab (anti-HER-2) can inhibit cardiacfunction, particularly in those patients with prior exposure to anthracyclines.Bevacizumab has a number of side effects of medical significance, includinghypertension, proteinuria, hemorrhage, and gastrointestinal perforations with orwithout prior surgeries. Conjugation of antibodies to drugs and toxins is discussed above;conjugates of antibodies with isotopes, photodynamic agents, and other killingmoieties may also be effective. Radioconjugates targeting CD20 on lymphomashave been approved for use [ibritumomab tiuxetan (Zevalin), using yttrium-90 or131 I-tositumomab]. Other conjugates are associated with problems that have not yetbeen solved (e.g., antigenicity, instability, poor tumor penetration). Cytokines There are >70 separate proteins and glycoproteins with biologic effects inhumans: interferon (IFN) α, β, γ; IL-1 through -29 (so far); the tumor necrosisfactor (TNF) family [including lymphotoxin, TNF-related apoptosis-inducingligand (TRAIL), CD40 ligand, and others]; and the chemokine family. Only afraction of these has been tested against cancer; only IFN-α and IL-2 are in routineclinical use. About 20 different genes encode IFN-α, and their biologic effects areindistinguishable. Interferon induces the expression of many genes, inhibitsprotein synthesis, and exerts a number of different effects on diverse cellularprocesses. Its antitumor effects appear to be antagonized in vitro by thymidine,suggesting that de novo thymidylate synthesis is also affected. The tworecombinant forms that are commercially available are IFN-α2a and -α2b. Ingeneral, interferon antitumor effects are dose-related, and IFN is most effective atits MTD. Interferon is not curative for any tumor but can induce partial responsesin follicular lymphoma, hairy cell leukemi ...