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Treatment - Biological Therapies

Although a few are cytotoxic, most of the agents under this category are biologic response modifiers (BRM) that alter the host response to cancer. They follow a dose optimum profile within a narrow concentration range rather than the highest tolerated dose without unacceptable toxicity seen with chemotherapeutic drugs. BRMs may show suboptimal effects at concentrations higher or lower than the dose optimum. A major goal of biologic therapy is to manipulate the host immune response to cancer.

Immunotherapy.

Tumor immunotherapy is used to stimulate effective immune responses to human tumors. Although the immune response will recognize and eliminate cancers in animals, as yet this approach has failed to be really effective in humans. Antitumor immune responses are often difficult to measure in cancer patients, and even if present, may not result in tumor rejection. From animal models it is known that tumor cell rejection is mediated primarily by cytotoxic T lymphocytes and natural killer cells. Helper T cells, B cells and macrophages are also involved.

Cellular Therapy. Active specific immunotherapy (adoptive cellular therapy) has used irradiated or chemically modified autochthonous or allogeneic tumor cells in an attempt to produce host immunity to tumors. A major limitation of this approach has been the availability of purified tumor-associated antigens, but the advent of synthesized and genetically engineered antigens, not to mention the use of idiotope vaccines, is generating new interest in the area. Purified interleukin-2 (IL-2) has been used to activate and expand a population of lymphocytes referred to as LAK cells (lymphokine activated killer cells) by culturing peripheral blood lymphocytes with IL-2 ex vivo. LAK cells can directly lyse freshly isolated solid tumor cells. LAK cells differ from natural killer cells and, when used combined with IL-2, have been found to produce complete and partial remissions in patients with advanced metastatic melanoma and renal cancers, particularly. LAK cells with IL-2 does not appear to be better than IL-2 alone. IL-2 can also be used to expand ex vivo tumor-infiltrating lymphocytes (TIL) directly isolated from solid tumors. TIL have significantly better antitumor effectiveness than LAK cells. It is not yet known whether TIL is more effective than IL-2 alone, but early clinical trials with disseminated melanoma are promising. Patients with chronic myeloid leukemia who have relapsed after bone marrow transplantation have been treated with allogeneic immune effector cells infused with donor-derived buffy coats. But myelosuppression and graft-versus-host disease can result.

Cytokines are intercelluar messenger immunomodulatory proteins that include the interferons and the interleukins. The thymosins also have immunologic activity; and thymosin alpha-1 and thymosin fraction 5 have had the most study. They can correct selected immunodeficiency states and can augment suppressed T-cell responses in patients with cancer. Clinical studies are ongoing. The lymphokines and the cytokines provide more than 20 categories of natural mediators that are now being made available through genetic engineering techniques. These are molecules secreted by a variety of cells, and they are one way by which immune cells communicate with one another and control the overall immune response. To date, the agents are used pharmacologically in high doses for their antiproliferative action rather than their immunomodulatory abilities. Use for the pharmacologic treatment of tumors of the lymphoid system is an important possibility. Several subclasses of colony-stimulating factors are being examined along with factors that control the proliferation and maturation of B-cells and macrophages.

The interferons are small proteins with antiviral, antiproliferative, and immunomodulatory activity. Type I interferons share a common cell receptor and include interferons alpha and beta. Interferon beta is the product of a single gene, but interferon alpha is the product of a multigene family with over 20 members. Alpha inteferon has shown activity in hairy cell leukemia, renal cell cancer, and several other tumors, especially hematologic malignancies. Recombinant interferon alpha is now used to treat chronic myeloid leukemia, hairy cell leukemia and AIDS-related Kaposi's sarcoma. It is used as an adjuvant in high risk melanoma and has activity in renal cell carcinoma, multiple myeloma and low grade non-Hodgkin's lymphoma. Although Type I interferons have both properties, it is still unclear whether they work primarily by their antiproliferative activity or through alterations of the regulation of immune responses. The beta and gamma interferons are also under study, with gamma interferon showing particular interest. Gamma interferon or type II interferon is produced by lymphocytes and has immunomodulatory properties that are different from those of type I interferons. It is used to treat chronic granulomatous disease, but its use with tumors remains experimental since it seems to have less antitumor activity than type I interferons. Combining interferons with chemotherapeutic agents and with other lymphokines and cytokines is being studied. The side effects of cytokines and lymphokines are considerable and require a highly specialized expertise to administer effectively, particularly if they are given with cellular therapy such as LAK cells.

The interleukins are cytokines that act as leukocyte intercellular messengers. Over 17 have been described and many are now being tested in clinical trials. Interleukin (IL)-2 or T-cell growth factor, is the best studied. It stimulates both the proliferation and the cytotoxicity of both T cells and natural killer cells, acting as a key regulatory hormone for cellular immunity. A few patients with disseminated renal cell carcinoma and melanoma respond to high dose IL-2, and perhaps 5 to 10% of these patients have a complete response with long term disease free survival. But the substance is very toxic and requires management in an intensive care unit. Less toxic regimens suitable for outpatient use involving continuous infusion at lower less toxic doses are being studied. IL-4 is secreted by T cells and mast cells and has diverse effects on the immune and hemopoietic systems. It is being used in early trials alone and with IL-2, but antitumor response rates are low. IL-6 is being studied in clinical trials for its antitumor and thrombopoietic effects. It is a pleiotropic cytokine with antiproliferative effects on model tumor systems and both immune and hemopoietic activities affecting B cells, T cells and megakaryocytes. IL-12 is being studied in phase I trials with AIDS and cancer. It stimulates both T cells and natural killer cells.

Lymphotoxin, a product of antigen- or mitigen-stimulated leukocytes and a principal effecter of the delayed hypersensitivity, is also under study. Tumor necrosis factor (TNF; alpha-lymphotoxin) is in early phase trials. It has a central role in inflammation, but is very toxic and has low tumor response rates. It isbeing studied for local and regional use, including isolated limb perfusion. Many of these cytokines such as TNF, interferon, and IL-2 are also being examined in combinations for complementary effects.

Monoclonal antibodies have become available in large quantities since the development of the hybridoma methodology in 1975. Because they react specifically to antigenic determinants there have been high expectations for their role as a "magic bullet" for cancer treatment. They are important for cancer diagnosis, but their role in cancer treatment has proved disappointing and is still experimental. Monoclonals react to tumor-associated antigens for tumors of the colon, lung, pancreas, and melanoma, and for leukemia and lymphomas. They are being studied clinically alone (umconjugated), but in this way have proved to be disappointing. As immunoconjugates they can be coupled with chemotherapeutic agents, toxins such as ricin or Pseudomonas toxin, or with radionuclides, especially alpha particle emitters. Temporary regressions have been seen in leukemia, lymphoma, melanoma, and hepatocellular carcinoma. Such antibodies are useful for radioimmunoimaging of tumor cell masses and for the removal of T-cells and tumor cells from bone marrow to improve bone marrow transplantation techniques. The heterogeneity of tumors and the vascular access of these agents to tumors still present major obstacles to be overcome. Cocktails of antibodies sufficient to cover the heterogeneity of the different tumor cell types, chosen by typing the tumor from each patient, may require an individualized approach to be effective. Several obstacles remain to be surmounted. Tumor-specific antigens can be difficult to define serologically. Target antigens may disappear form the surface of tumor cells (antigenic modulation). Monoclonals made in mice are themselves immunogenic and the development of human anti-mouse antibodies (HAMA) limit their effectiveness. Attempts are being made to "humanize" monoclonals by genetic engineering.

However, monoclonals have proven to be very useful diagnostically. Immunophenotyping leukemias and lymphomas with monoclonals to myeloid and lymphoid differentiation antigens helps in classification, diagnosis, prognosis and treatment of these disorders and has contributed to understanding of their pathogenesis. Monoclonals are used in serum assays for tumor markers to follow disease progress in solid tumors. Assays for carcinoembryonic antigen (CEA) (colorectal and breast cancers), CA-125 (ovarian cancer) and prostate-specific antigen (PSA) (prostate cancer) are examples.

Tumor vaccines are undergoing a resurgence of interest in the 1990's after their lack of success in the 1970s with advances in immunology and molecular biology. Immunization with syngeneic tumors will protect animals from subsequent tumor challenge. But vaccines are effective only with minimal disease in the adjuvant setting. Identification of optimal antigens and immunogens remains a problem. Some patients with melanoma have had modest tumor responses of short duration to injections of autologous whole tumor cells, unmodified, modified (conjugated with DNP or treated with neuraminidase), or mixed with an immune adjuvant like BCG. Efforts are now being made to enhance the immunogenicity of the autologous tumor by inducing it to express immunomodulatory molecules like IL-2, GM-CSF or B7 using gene transfer techniques.

Hemopoietic Growth Factors

Various forms of colony-stimulating factor (CSF) are being examined for their ability to correct cytopenias related to myelodysplastic syndromes, leukemias, and treatments with chemotherapy. CSFs are cytokines that regulate growth and differentiation of the hemopoietic system. Granulocyte-macrophage CSF (GM-CSF) supports neutrophil maturation by stimulating the differentiation of committed myeloid progenitors into mature granulocytes, monocytes and eosinophils. Therecombinant form is used to hasten the reconstitution of bone marrow after autologous bone marrow transplantation. Granulocyte CSF (G-CSF) promotes the growth and differentiation of committed neutrophilic progenitor cells, and is given to shorten the period of neutropenia resulting from bome marrow suppression from chemotherapy. Interleukin 3 promotes growth and differentiation of multipotential hematopoietic precursors and also erythroid, myeloid and megakaryocytic commtted progenitors, but results from clinical trials have been disappointing.

Erythropoietin is the major regulator of erythropoiesis. It promotes erythroid maturation in committed progenitor cells and stumulates the relase of reticulocytes from the bone marrow. The hormone is produced by the kidney and the liver in response to hypoxia. The recombinant form is used to treat the anemia of chronic renal failure. It is somewhat helpful in relieving anemia due to chemotherapy but does not help the anemia of chronic disease seen in cancer.

Thrombopoietin (Mpl ligand) promotes the maturation of megakaryocytes and the production of platelets. Clinical trials are only beginning. Other cytokines that maintain multipotent hemopoietic stem cells are also beginning to be tested. They include the Flk2/Flt3 ligand and stem-cell or Steel factor, both of which activate specific tyrosine kinase receptors that are restricted to the earliest stem cells. They synergize woith later-acting IL-3 or GM-CSF the stimulate proliferation and expansion of hemopoietic progenitors.

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