Chapter 081. Principles of Cancer Treatment (Part 25) docx

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.. How

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 using antibodies where the antigen-combining regions are grafted onto human immunoglobulin gene products (chimerized or humanized), or derive de novo from mice bearing human immunoglobulin gene loci Such humanized antibodies against the CD20 molecule expressed on B cell lymphomas (rituximab) and against the HER-2/neu receptor overexpressed on epithelial cancers, especially breast cancer (trastuzumab), have become reliable tools in the oncologist's armamentarium Each used alone can cause tumor regression (rituximab more than trastuzumab), and both appear to potentiate the effects of combination chemotherapy given just after antibody administration Antibodies to CD52 are active in chronic lymphoid leukemia and

T cell malignancies EGF-R–directed antibodies (such as cetuximab and panitumomab) have activity in colorectal cancer refractory to chemotherapy, particularly when utilized to augment the activity of an additional chemotherapy program, and in the primary treatment of head and neck cancers treated with radiation therapy The mechanism of action is unclear Direct effects on the tumor may mediate an antiproliferative effect as well as stimulate the participation of host mechanisms involving immune cell or complement-mediated response to tumor cell–bound antibody Alternatively, the antibody may alter the release of paracrine factors promoting tumor cell survival

The anti-VEGF antibody bevacizumab shows little evidence of antitumor effect when used alone, but when combined with chemotherapeutic agents it

improves the magnitude of tumor shrinkage and time to disease progression in colorectal, lung, and breast cancer The mechanism for the effect is unclear and may relate to the capacity of the antibody to alter delivery and tumor uptake of the active chemotherapeutic agent

Side effects include infusion–related hypersensitivity reactions, usually limited to the first infusion, which can be managed with glucocorticoid and/or antihistamine prophylaxis In addition, distinct syndromes have emerged with different antibodies Anti-EGF-R antibodies produce an acneiform rash that poorly responds to steroid cream treatment Trastuzumab (anti-HER-2) can inhibit cardiac function, particularly in those patients with prior exposure to anthracyclines Bevacizumab has a number of side effects of medical significance, including hypertension, proteinuria, hemorrhage, and gastrointestinal perforations with or without prior surgeries

Conjugation of antibodies to drugs and toxins is discussed above; conjugates of antibodies with isotopes, photodynamic agents, and other killing moieties may also be effective Radioconjugates targeting CD20 on lymphomas have been approved for use [ibritumomab tiuxetan (Zevalin), using yttrium-90 or

131

I-tositumomab] Other conjugates are associated with problems that have not yet been solved (e.g., antigenicity, instability, poor tumor penetration)

Cytokines

There are >70 separate proteins and glycoproteins with biologic effects in humans: interferon (IFN) α, β, γ; IL-1 through -29 (so far); the tumor necrosis factor (TNF) family [including lymphotoxin, TNF-related apoptosis-inducing ligand (TRAIL), CD40 ligand, and others]; and the chemokine family Only a fraction of these has been tested against cancer; only IFN-α and IL-2 are in routine clinical use

About 20 different genes encode IFN-α, and their biologic effects are indistinguishable Interferon induces the expression of many genes, inhibits protein synthesis, and exerts a number of different effects on diverse cellular processes Its antitumor effects appear to be antagonized in vitro by thymidine, suggesting that de novo thymidylate synthesis is also affected The two recombinant forms that are commercially available are IFN-α2a and -α2b In general, interferon antitumor effects are dose-related, and IFN is most effective at its MTD Interferon is not curative for any tumor but can induce partial responses

in follicular lymphoma, hairy cell leukemia, CML, melanoma, and Kaposi's sarcoma It has been used in the adjuvant setting in stage II melanoma, multiple myeloma, and follicular lymphoma, with uncertain effects on survival It produces fever, fatigue, a flulike syndrome, malaise, myelosuppression, and depression and can induce clinically significant autoimmune disease

IL-2 must exert its antitumor effects indirectly through augmentation of immune function Its biologic activity is to promote the growth and activity of T

cells and natural killer (NK) cells High doses of IL-2 can produce tumor regression in certain patients with metastatic melanoma and renal cell cancer About 2–5% of patients may experience complete remissions that are durable, unlike any other treatment for these tumors IL-2 is associated with myriad clinical side effects: intravascular volume depletion, capillary leak syndrome, adult respiratory distress syndrome, hypotension, fever, chills, skin rash, and impaired renal and liver function Patients may require blood pressure support and intensive care to manage the toxicity However, once the agent is stopped, most of the toxicities reverse completely within 3–6 days

Gene Therapies

No gene therapy has been approved for routine clinical use Several strategies are under evaluation, including the use of viruses that cannot replicate to express genes that can allow the action of drugs or directly inhibit cancer cell growth, viruses that can actually replicate but only in the context of the tumor cell,

or viruses that can express antigens in the context of the tumor and therefore provoke a host-mediated immune response Key issues in the success of these approaches will be in defining safe viral vector systems that escape host immune function and effectively target the tumor or tumor cell milieu Other gene therapy strategies would utilize therapeutic oligonucleotides to target the expression of genes important in the maintenance of tumor cell viability

Acknowledgments

Stephen M Hahn, MD, and Eli Glatstein, MD, contributed a chapter on radiation therapy in the prior edition, and some of their material has been incorporated into this chapter

Further Readings

American Society of Clinical Oncology: 2006 Update of recommendations for the use of white blood cell growth factors: An evidence-based clinical practice guideline J Clin Oncol 24:3187, 2006

———: Guideline for antiemetics in oncology: Update 2006 J Clin Oncol 24:2932, 2006

Chabner BA, Longo DL (eds): Cancer Chemotherapy and Biotherapy:

Principles and Practice, 4th ed Philadelphia, Lippincott Williams & Wilkins,

2006

Folkman J: Angiogenesis: An organizing principle for drug discovery? Nat Rev Drug Discov 6:273, 2007 [PMID: 17396134]

Krause DS, Van Etten RA: Tyrosine kinases as targets for cancer therapy

N Engl J Med 353:17, 2005