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Special Address: A Novel Approach to Cancer Treatment Based on Immune Stimulation and Other Environmental Approaches

Steven Rosenberg

The history of cancer treatment has evolved over the years. Surgery, sometimes quite primitive, began more than 3,000 years ago. Just a year after the discovery of radiation therapy by Roentgen in 1895, a Chicago physician treated a patient with advanced breast cancer by exposing the chest wall to radiation and in fact saw tumor regression; thus began modern radiation therapy. Chemotherapy began about 60 years ago predominantly as a result of a 1942 laboratory accident involving the development of nerve gas that exposed workers to nitrogen mustard. It was noted that these individuals developed a lymphopenia and a decrease in circulating numbers of lymphocytes. This led a Yale physician, G.D. Lindskog, to use this material to treat a patient with what was then known as an “X-ray resistant lymphosarcoma,” and he saw a dramatic regression of that lymphoma. This led to the realization that chemicals could be used to cause cancer regression, and that has led to a substantial amount of work in the last 60 years attempting to develop inorganic molecules that might be used for treating patients with a variety of malignancies.

Today, the appropriate application of surgery, radiation therapy, and chemotherapy can cure about half of all individuals who develop cancer. However, the half of cancer patients who cannot be cured by these methods accounted for almost 600,000 deaths in 2000, which points to the need for the development of new approaches to treat cancer. One of these approaches is biologic therapy, that is, treatments that act primarily through natural host defense mechanisms or by the administration of natural mammalian substances. In biologic therapies, we take advantage of the body’s own natural defense mechanisms to reject the cancer.

An issue that has plagued the field of tumor immunology is whether it is possible to use the immune system to cause the regression of established human cancers. Historically, there has been a great deal of skepticism about this possi-



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Cancer and the Environment: Gene-Enviroment Interaction 6 Special Address: A Novel Approach to Cancer Treatment Based on Immune Stimulation and Other Environmental Approaches Steven Rosenberg The history of cancer treatment has evolved over the years. Surgery, sometimes quite primitive, began more than 3,000 years ago. Just a year after the discovery of radiation therapy by Roentgen in 1895, a Chicago physician treated a patient with advanced breast cancer by exposing the chest wall to radiation and in fact saw tumor regression; thus began modern radiation therapy. Chemotherapy began about 60 years ago predominantly as a result of a 1942 laboratory accident involving the development of nerve gas that exposed workers to nitrogen mustard. It was noted that these individuals developed a lymphopenia and a decrease in circulating numbers of lymphocytes. This led a Yale physician, G.D. Lindskog, to use this material to treat a patient with what was then known as an “X-ray resistant lymphosarcoma,” and he saw a dramatic regression of that lymphoma. This led to the realization that chemicals could be used to cause cancer regression, and that has led to a substantial amount of work in the last 60 years attempting to develop inorganic molecules that might be used for treating patients with a variety of malignancies. Today, the appropriate application of surgery, radiation therapy, and chemotherapy can cure about half of all individuals who develop cancer. However, the half of cancer patients who cannot be cured by these methods accounted for almost 600,000 deaths in 2000, which points to the need for the development of new approaches to treat cancer. One of these approaches is biologic therapy, that is, treatments that act primarily through natural host defense mechanisms or by the administration of natural mammalian substances. In biologic therapies, we take advantage of the body’s own natural defense mechanisms to reject the cancer. An issue that has plagued the field of tumor immunology is whether it is possible to use the immune system to cause the regression of established human cancers. Historically, there has been a great deal of skepticism about this possi-

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Cancer and the Environment: Gene-Enviroment Interaction bility. However, studies of the cytokine interleukin-2, produced by human lymphocytes, reveal that it is a natural body substance that plays a predominant role in regulating the immune response in humans and other mammals. Interleukin-2 has no direct impact on cancer cells. Cancer cells can be incubated in the highest achievable concentrations of interleukin-2 with no impact on the growth of the cells. All of the impact of interleukin-2 occurs because of its ability to mediate immune reactions in the body and alter the body’s own natural defenses to attack the cancer. The National Cancer Institute has treated more than 400 metastatic melanoma and metastatic kidney cancer patients with interleukin-2 alone. About 15 percent of patients with metastatic melanoma show an objective regression, that is, at least 50 percent of the tumor disappears, and in half of those patients all of the cancer will disappear. In kidney cancer patients, about 20 percent show complete regressions. This then is the proof of principle that it is possible to use the body’s immune system to cause cancer regression. If we can understand the mechanisms by which the body rejects these cancers, we might then be able to extend this to patients with other types of cancer. Prior to these studies it was thought that large solid tumors could not be attacked by the immune system, but success in achieving complete regression of all metastatic disease in the lung and liver has been demonstrated. Bony metastases can also respond to this treatment. What are the antigens involved in cancer regression? We identified a kind of cell, a tumor infiltrating lymphocyte (TIL), which invades tumors and is part of the body’s reaction against these tumors. TILs obtained from patients with melanoma were then used to identify the genes encoding the antigens recognized by these TILs. TILs have been identified that can recognize unique cancer antigens on murine and human cancers, including melanoma, breast cancer, colon cancer, and lymphoma. In clinical trials of TIL administration, 36 percent of patients with metastatic melanoma underwent objective cancer remission. To determine whether the identified genes actually encoded cancer regression antigens, patients were immunized with the gene products to determine whether the regression of growing cancers could be induced. Alternatively, in vitro lymphocytes sensitized against the putative cancer regression antigens were generated and adoptively transferred into patients to determine whether they could mediate cancer regression. Through the use of a genetic technique that enables the expression cloning of genes encoding antigens recognized by CD4+ immune cells, we have been able to identify several new class II (MNC) restricted tumor antigens. Several of these are tissue-specific. It is thought that some of these tissue-specific proteins in tumors derived from nonessential organs can serve as the targets for immunotherapy. Cancer antigens can arise from a variety of different cellular events. A single cancer antigen contains peptides that can be presented on many different

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Cancer and the Environment: Gene-Enviroment Interaction types of MNC molecules. Individual patients can react against multiple antigens. It is the cellular arm of the immune response that is predominantly involved in immune reactivities, and a key question is whether we can use this information to generate antitumor T cells by immunizing patients using a vaccine. In a pilot trial, we demonstrated that a modified peptide could consistently immunize cancer patients and generate T cells in their circulation that can recognize the cancer. Work by us and others has opened new possibilities for the development of effective immunotherapies for the treatment of cancer.