We now look at how immunotherapy has been used in conventional cancer medicine. From this discussion, we obtain ideas on how natural compounds might be used to produce some of the same effects on the immune system, and we also see how the use of natural compounds differs from that of most conventional immunotherapy agents. The primary distinction between conventional immunotherapy agents and natural immunostimulant compounds is that the former tend to be cells or cyto-kines activated or generated outside the body, then injected into it, whereas the natural compounds cause the body to produce its own activated cells and cytokines. Still, the research showing that externally administered cells or cytokines can have an effect on cancer implies that natural compounds have the potential to produce the same effect.
The majority of human cancers exhibit low immuno-genicity, probably due to one or more of the immune-evading mechanisms described earlier. This does not mean, however, that immunotherapy is necessarily ineffective against them. Conventional immunotherapy can be divided into two categories, active and passive, each discussed below. In general, conventional immunother-apy in humans is most effective in patients with a relatively healthy immune system and a low tumor burden (i.e., at an early stage of malignancy).
The term active immunotherapy refers to methods that directly stimulate an immune response by the body. In conventional medicine, this is often accomplished through immunization with damaged (nonviable) tumor cells or by injection of bacterial antigens, such as microbial agents. Examples of this type of therapy are the administration of Coley's toxins and the BCG bacterial product. (Recall that macrophages are activated by bacterial antigens.)
The clinical role of active immunotherapy as a sole agent may be limited, since prior to therapy the patient's immune system has had ample time to recognize and react to tumor antigens. Nonetheless, the use of various active immunotherapy agents has had some limited success in treating patients with osteosarcoma, leukemia, lymphoma, melanoma, and lung, kidney, bladder, ovarian, colon, and breast cancer.30-33 Kidney cancer and melanoma exhibit the greatest immunogenicity and may respond better to active immunotherapy than other cancers. Also, transitional cell carcinoma of the bladder responds well to BCG bacterial products.34 (In this case, the bacterial products are applied directly to the tumor.) In general, however, tumor-induced immunosuppression must be removed or reduced for active immunization to be successful.
Passive immunotherapy refers to administration of agents that passively increase immune activity. Passive immunotherapy includes administration of serum or immune cells from immunized animals; administration of cloned antibodies; and administration of cloned im mune cells and cytokines. Of these, passive immunotherapy with cloned immune cells or cytokines or both seems the most promising.
Two types of cloned cells have been investigated: tumor-infiltrating lymphocytes (TIL) and lymphokine-activated killer (LAK) cells. TIL therapy involves removing the T lymphocytes that migrate into solid tumors, cloning and activating them with IL-2, and then re-injecting them into the patient. The idea is that the T cells taken from inside the tumor, and their subsequent clones, are already sensitized to the tumor. TIL therapy has had some success against melanoma. LAK cell therapy is similar to TIL therapy, except that NK cells are used and the cells are obtained from the general circulation rather than from inside the tumor. LAK cells act similar to but are more active than NK cells. The cloning and activation of LAK cells in culture is made possible by the administration of IL-2.
Generating TIL and LAK cells and then injecting them into the body has relevance to the use of natural immu-nostimulant compounds, since both involve using cyto-kines to activate immune cells (one outside the body and one inside). As discussed in Chapter 12, a number of natural compounds increase production of IL-2, interferons, and other cytokines. Administration of these cytokines in their pure form can modestly affect some cancers (see below), and it seems reasonable that increasing their internal production using natural compounds will also modestly affect some cancers. It is also reasonable to suppose that the anticancer effects will be greater when these compounds are combined with ones that inhibit immune evasion and those that deter cancer by other means, such as inhibition of signal transduc-tion.
A number of clinical trials have administered IL-2 alone or in combination with LAK cells.35-39 Although IL-2 immune stimulation holds promise, so far the results have been modest. In past studies, the average total response rate has been roughly 20 to 30 percent, with the majority of these partial responses. For example, IL-2, with or without LAK cells, produced a response in up to 30 percent of patients with kidney cancer, but only 5 to 10 percent achieved long-lasting complete re-sponses.41 The clinical gains were modest in spite of the fact that immune function, as measured by NK cell activity, was successfully stimulated in the majority of patients.36'38 This again suggests that to obtain optimal clinical results, it may be necessary to combine immuno-therapy with other anticancer therapies, including therapies that limit immune evasion.
Although IL-2 is a naturally occurring substance in the body, its use at high concentration produces serious, sometimes life-threatening, adverse effects. These effects are apparently due partly to increases in capillary permeability caused by IL-2. However, newer approaches, employing lower doses of IL-2 given intravenously or subcutaneously, may circumvent some of these problems. These newer approaches more closely mimic the increase in IL-2 concentrations that would be produced by the use of natural compounds (i.e., more gradual increases and lower peak concentrations).
Interferons (IFNs) have been the most extensively studied cytokines in cancer treatment. As a group, interferons affect a wide array of immunological functions. They mediate antiviral and antimicrobial activity, stimulate or inhibit leukocyte proliferation, suppress onco-genes, enhance tumor antigen expression, suppress angiogenesis, and augment the activity of NK cells, T lymphocytes, and macrophages. Interferons and tumor necrosis factor (TNF) also increase the burning of body fat stores, possibly to release energy reserves from fat cells for the immune system to use. In this capacity, they play a role in the development of cachexia (tissue wasting disease). Although this is a drawback to their use, interferons still produce an anticancer effect at tolerable doses.
Interferons have been effective against some nonsolid tumors such as hairy cell leukemia (85 percent response rate), chronic myelogenous leukemia (75 percent), and nodular lymphoma (45 percent).40 Injections are usually administered daily for prolonged periods. Interferons are ineffective against chronic lymphocytic leukemia and multiple myeloma, but in the latter, administration of interferons may prolong the duration of chemotherapy-induced remission. Solid tumors respond less favorably to interferon therapy. Responses have been observed in Kaposi's sarcoma (33 percent response rate), brain cancer (40 percent), gastrointestinal cancers (20 percent), melanoma (15 percent), and kidney cancers (20 percent). As with IL-2, most of these responses were partial. In the case of kidney cancer, only about 3 to 5 percent of patients achieve long-lasting complete responses.41 Local injection, as opposed to systemic therapy, has been used with some success against basal cell carcinoma (75 percent response rate), bladder cancer (40 percent), and ovarian cancer (45 percent).
Although life-threatening complications are rare from interferon administration, quality of life is commonly impaired because of fever, chills, headache, fatigue, anorexia, nausea, and other side effects. Some of these side effects may be due to increased secretion of tumor necrosis factor by stimulated macrophages.
The results of clinical trials using individual cytokines such as IL-2 have been modest. Recent studies, however, have employed cocktails of cytokines and chemotherapy agents and the results of these trials are more promising. For example, studies have reported that the combination of chemotherapy with IL-2 and IFN-alpha produced responses in more than 50 percent of patients with metastatic melanoma, and approximately 10 percent achieved long-lasting complete responses.42'43 This again supports the concept that combinations of natural compounds that both stimulate the immune system and inhibit cancer by other means may be most effective. Importantly, natural immunostimulant compounds tend to stimulate a broad-based increase in cytokine production (see Chapter 12). Production of interleukins, interferons, and colony-stimulating factors may all be increased. In this way, such immunostimulants may naturally produce their own cocktail of cancer-fighting compounds.
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