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MEDICAL BIOLOGY: ON CANCER IMMUNOTHERAPY

The following points are made by Steven A. Rosenberg (New Engl. J. Med. 2004 350:1461):

1) The realization that human cancers express cancer-associated antigens has stimulated research into the development of immunotherapies to mediate the regression of established tumors. There are three requirements for an effective immunotherapy for cancer. A sufficient number of avid tumor-reactive lymphocytes must be present in the tumor-bearing host, these lymphocytes must be capable of reaching and extravasating at the site of the cancer, and the lymphocytes at the tumor site must have appropriate effector mechanisms to destroy cancer cells.

2) A recent study goes some way toward understanding the second requirement. Yu et al(1) show that inserting a gene encoding a member of the tumor necrosis factor superfamily, referred to as TNFSF-14, or LIGHT, into a mouse tumor-cell line that was engineered to express an alloantigen (called H-2d) prevents the cell line from establishing a tumor when it is injected into mice. LIGHT acts as a tether between the tumor stroma and T lymphocytes; it binds receptors on each. Stimulation of the stromal receptor triggers the up-regulation of molecules that help to attract T lymphocytes, thus increasing the infiltration of lymphocytes into the growing tumor that expresses LIGHT and priming these lymphocytes to react against and destroy the tumor. Preliminary experiments suggest that distant tumors might be affected as well.

3) A variety of problems, however, have plagued the translation of results obtained in animal models into effective immune-based treatments of cancer in humans; the study by Yu et al(1) is not exempt from these problems. The authors focus mainly on immunization strategies that can prevent the establishment and outgrowth of a transplanted tumor, but effecting the regression of established, invasive, vascularized cancers is more difficult, since the three requirements must be met and there are currently no immunization strategies capable of meeting them. And although the genetic tweak engineered by Yu et al(1) is sufficient to trigger an effective host response to a tumor bearing the H-2d alloantigen, this strong antigen is an unrealistic surrogate for human cancer antigens. Most human cancer antigens are normal, nonmutated differentiation molecules or nonmutated proteins found only in tumor or germ cells; the human immune system seems to be more tolerant of these antigens than the mouse system is of alloantigen.

4) No experiments in mouse models have demonstrated that immunization against cancer (through the use of cancer vaccines) can reproducibly result in the destruction of large, well-vascularized mouse tumors expressing natural, nonmutated antigens. It therefore comes as no surprise that efforts to develop therapeutic cancer vaccines in humans have been unsuccessful thus far. Although large numbers of circulating T lymphocytes capable of recognizing cancer antigens can be induced in patients with cancer, especially by immunization with peptides emulsified in immune adjuvants, only rare and sporadic regressions of established tumors that meet rigorous oncologic criteria for a clinical response have been reported.(2-5)

References:

1. Yu P, Lee Y, Liu W, et al. Priming of naive T cells inside tumors leads to eradication of established tumors. Nat Immunol 2004;5:141-149

2. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 1998;4:321-327

3. Khong HT, Restifo N. Natural selection of tumor variants in the generation of "tumor escape" phenotypes. Nat Immunol 2002;3:999-1005

4. Overwijk WW, Theoret MR, Finkelstein SE, et al. Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. J Exp Med 2003;198:569-580

5. Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002;298:850-854

New Engl. J. Med. http://www.nejm.org

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MEDICAL BIOLOGY: ON IMMUNOTHERAPY

The following points are made by R.M. Steinman and I. Mellman (Science 2004 305:197):

1) The term "immunotherapy" refers to any approach aimed at mobilizing or manipulating a patient's immune system to treat or cure disease. Although the term has been most often associated with therapies for established malignancies (1-5), immunotherapy is of increasing interest as an approach to arrest cancer at a much earlier stage. In addition, immunotherapy is pertinent to the investigation and treatment of transplantation, autoimmunity, chronic inflammation, and infectious disease. In general, the strategies range from therapeutic vaccines that mobilize a patient's own immune system de novo (so called "active" immunotherapy), to administration of preformed biological reagents such as monoclonal antibodies, cytokines, or previously activated immune cells ("passive" immunotherapy) that deliver or modulate a specific arm of the systemic immune response.

2) The field of immunotherapy is often characterized by the term "translational research". Although this term telegraphs a well-intentioned desire to directly transfer basic discoveries from the laboratory to the clinic, it also connotes a problem. "Translation" ignores the fact that investigation in the clinic and the laboratory is a two-way street, with information learned in humans often generating new avenues of investigation in model organisms, such as mice. Moreover, and of equal concern, "translation" implies that basic principles learned elsewhere (often in mice) are directly applicable to humans. If only it were this simple.

3) To be successful, immunotherapy requires a broadening of basic research in humans. Not enough is known about how the human immune system works or how it responds, not just to cancer but to many other diseases, such as autoimmune disorders and allergy. For example, spontaneous human malignancies differ fundamentally from experimental mouse tumors, and the human and mouse immune systems differ considerably from one another. Equally important, having therapy as the only aim of human immunology research overlooks the need to understand the properties of the human immune system that resist cancer or allow the disease to progress. We need an approach that fosters the pursuit of basic discovery in the clinic and eliminates the basic versus applied distinction implied by the term "translation."

4) Immunotherapy lends itself to such basic research in patients, since the immune system can often be assessed and even manipulated with relatively few risks. In the case of cancer, three known features of the disease set the stage for basic discoveries in immunology. First, the changes that drive cancer, often genetic, also generate new antigens that can be and are recognized by the immune system. Second, tumor cells as well as their supporting vessels and environment (stroma) can be highly sensitive to, and also can alter, the array of immune cells and their products. Third, the progression of cancer may rely upon direct or indirect evasion of the immune system by the tumor cells. The view of the authors is that the time is ripe to obtain a better scientific understanding of these features in patients and ensure a more comprehensive view of cancer and other diseases. To do so, we first need to acknowledge the obstacles and then bring about some changes.

5) In summary: The field of immunotherapy holds clear promise not only for the development of new approaches to cancer and other diseases, but also for providing fundamental insight into the human immune response. In order for this promise to be realized, however, the scientific community must overcome an array of challenges. These challenges reflect not only the difficulties inherent in conducting investigations in human patients, but also difficulties created by the culture and practice of our own institutions, reward structure, and funding mechanisms. The authors suggest steps to be taken to reinvigorate basic research in human subjects as part of the mainstream of science.

References (abridged):

1. D. M. Pardoll, Nat. Rev. Immunol. 2, 227 (2002)

2. M. A. Perales et al., Semin. Cancer Biol. 12, 63 (2002)

3. M. E. Dudley, S. A. Rosenberg, Nat. Rev. Cancer 3, 666 (2003)

4. T. A. Waldmann, Nat. Med. 9, 269 (2003)

5. C. G. Figdor, I. J. M. de Vries, W. J. Lesterhuis, C. J. M. Melief, Nat. Med. 10, 475 (2004)

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