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Editorial |
Department of Surgery, New York University School of Medicine, 160 East 34th Street, NYU Clinical Cancer Center, Third Floor, New York, New York 10016
Correspondence: Address correspondence and reprint requests to: Kristin A. Skinner, MD; E-mail: kristin.skinner{at}med.nyu.edu.
Cancer research over the past 50 years has led to the development of a wide variety of therapeutics. Most common cancer treatments capitalize on the proliferation differential between healthy and malignant tissues and target rapidly dividing cells. Such treatments have had a significant effect on cancer survival, but they are also responsible for major toxicities, because some healthy tissues are also rapidly dividing. Despite the advances in cancer therapeutics, cancer remains a leading cause of death and disability. Malignant transformation is a complex process that involves not only increased cell proliferation and escape from normal regulation, but also alterations in gene expression and in cell/matrix interactions. This leads to a loss of differentiation, invasion of surrounding tissues, loss of anchorage dependence, angiogenesis, metastasis formation, and evasion of the host immune system. Current research strategies are attempting to target these nonproliferative aspects of the cancer phenotype in hopes of developing more specific and less toxic treatments.
Cancer immunotherapy attempts to harness the body’s natural defense system to destroy cancer cells. Approaches include passive immunotherapy, which nonspecifically stimulates the immune system, and active specific immunotherapy (vaccine therapy), which targets specific tumor-associated antigens to elicit a specific antitumor response. Historically, cancer immunotherapy has been focused on the more immunogenic tumors, such as melanoma and renal cell carcinoma. To date, the only passive immunotherapeutic approach that has been proven effective in a large prospective randomized trial is the use of high-dose interferon alfa in melanoma.1 Although passive immunotherapy has antitumor effects in patients with relatively immunogenic tumors, it has significant toxicity related to the nonspecific immunostimulation and is unlikely to be of benefit in most tumors that do not elicit a significant native immune response.
Active specific immunotherapy (vaccine therapy) is a more attractive therapeutic option in that it specifically targets tumor cells and so should be more effective with minimal toxicity. The use of trastuzumab in patients with Her2/neu–overexpressing breast cancers has been a significant success for the active specific immunotherapeutic approach.2 Over the past 25 years, active specific immunotherapy has evolved from the use of expanded populations of tumor-infiltrating lymphocytes to the use of tumor-specific antibodies and vaccines composed of whole or lysed tumor cells, tumor-specific antigens, peptides, or primed antigen-presenting cells (see review3). Whereas all of these approaches have shown benefit in animal models, most have not been proven effective in large randomized trials in humans, even in the most immunogenic of tumors.3–6 This failure in human studies is a function both of trial design, using vaccines in advanced cancers where there is bulky disease and systemic immunosuppression, and of the inherent heterogeneity in the patient population and in the tumors themselves.
Most cancers are not immunogenic, having developed the ability to evade the host immune system. Tumors cells avoid immunodestruction through a variety of mechanisms (see review7). Most tumor-associated antigens are the products of normal genes and so are protected by central and peripheral tolerance to self antigens. Further, most tumor-associated antigens are not critical for tumor cell growth and are easily lost or downregulated under the selective pressure of immune attack. Many tumors have loss-of-function genetic alterations in the antigen-processing and -presentation machinery, so that tumor-associated antigens cannot stimulate an effective immune response. Finally, tumors often secrete immunosuppressive cytokines or express lymphotoxic molecules such as Fas ligand.
An effective vaccine must target an appropriate antigen, must evoke a tumor-specific immune response, and must lead to the eradication of tumor cells or the prevention of tumor recurrence. In this issue of Annals of Surgical Oncology, Viehl et al.8 describe an elegant series of experiments documenting the efficacy of a vaccine using Her2/neu-Tat fusion protein–transduced dendritic cells against a breast cancer tumor cell challenge in mice. This vaccine is particularly well designed because it counteracts several of the tolerance mechanisms. By choosing Her2/neu as the target, they have selected a tumor-associated antigen that is overexpressed in a significant portion of several different tumor types. Furthermore, Her2/neu overexpression contributes to the malignant phenotype,9 so that downregulation under selective immune pressure is less of a problem. The use of a Tat fusion protein permits rapid transduction of mammalian cells,10 and its use with dendritic cells allows activation of both the major histocompatibility class I and class II pathways of antigen processing and presentation,11 so antigen presentation and immunostimulation can be maximized. The authors have documented successful transduction of the dendritic cells, migration of the primed dendritic cells to the secondary lymphoid organs, induction of tumor-specific CD8+ and CD4+ T-cell responses, and delayed induction of tumors in immunized animals after a tumor challenge. These data show promise for the development of a viable vaccine for breast cancer, a relatively nonimmunogenic tumor.
This article is an example of state-of-the-art designer vaccines that make the most of ongoing research in tumor immunology. As we continue to work on identifying appropriate tumor-associated antigens to target and to develop models and methods to overcome the issues of tumor and host heterogeneity, cancer vaccine therapy may become an effective therapy in men as well as in mice.
Received for publication March 25, 2005. Accepted for publication April 17, 2005.
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