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A number of immunologic interventions, both passive and active, can be directed against tumor cells.
Passive Cellular
Immunotherapy
In passive cellular immunotherapy, specific effector cells are directly infused and are not induced or expanded within the patient.
Lymphokine-activated killer (LAK) cells are produced from the patient's endogenous T cells, which are extracted and grown in a cell culture system by exposing them to the lymphokine IL-2. The proliferated LAK cells are then returned to the patient's bloodstream. Animal studies have shown that LAK cells are more effective against cancer cells than are the original endogenous T cells, presumably because of their greater number. Clinical trials of LAK cells in humans are ongoing.
Tumor-infiltrating lymphocytes (TILs) may have greater tumoricidal activity than LAK cells. These cells are grown in culture in a manner similar to LAK cells. However, the progenitor cells consist of T cells that are isolated from resected tumor tissue. This process theoretically provides a line of T cells that has greater tumor specificity than those obtained from the bloodstream.
Concomitant use of interferon enhances the expression of major histocompatibility complex (MHC) antigens and tumor-associated antigens (TAAs) on tumor cells, thereby augmenting the killing of tumor cells by the infused effector cells. However, remissions using these agents have been infrequent. A new approach using T cells genetically modified to express receptors that recognize TAAs with high specificity to tumor cells is under study and may provide significant clinical benefit.
Passive Humoral
Immunotherapy
Administration of exogenous antibodies constitutes passive humoral immunotherapy. Antilymphocyte serum has been used in the treatment of chronic lymphocytic leukemia and in T-cell and B-cell lymphomas, resulting in temporary decreases in lymphocyte counts or lymph node size.
Monoclonal antitumor antibodies may also be conjugated with toxins (eg, ricin, diphtheria) or with radioisotopes so that the antibodies deliver these toxic agents specifically to the tumor cells. Another technique involves bispecific antibodies, or linkage of one antibody that reacts with the tumor cell to a second antibody that reacts with a cytotoxic effector cell. This technique brings the effector cell in close opposition to the tumor cell, resulting in increased tumoricidal activity. However, these techniques are in the very early stages of testing; thus potential clinical benefits are uncertain.
Active
Specific Immunotherapy
Approaches designed to induce cellular immunity in the tumor-bearing host are more promising than are passive immunotherapy techniques. Inducing immunity in a host that failed to spontaneously develop an effective response generally involves methods to enhance presentation of tumor antigens to host effector cells.
Autochthonous tumor cells (cells taken from the host) have been reintroduced to the host after use of ex vivo techniques (eg, irradiation, neuraminidase treatment, hapten conjugation, hybridization with other cell lines) to reduce their malignant potential and increase their antigenic activity. Genetic modulation of the tumor cells to produce immunostimulatory molecules (including cytokines such as granulocyte-macrophage colony-stimulating factor [GM-CSF] or IL-2, costimulatory molecules such as B7-1, and allogeneic class I MHC molecules) can also be performed to attract effector molecules and enhance systemic tumor targeting. Recent clinical trials with GM-CSF–modified tumor cells have produced very encouraging preliminary results.
Allogeneic tumor cells (cells taken from other patients) have been used in patients with acute lymphocytic leukemia and acute myeloblastic leukemia. Remission is induced by intensive chemotherapy and radiation therapy; irradiated allogeneic tumor cells that have been modified either genetically or chemically to increase their immunogenic potential are injected into the patient. Alternatively, allogeneic tumor cells can be injected along with bacille Calmette-Guérin (BCG) vaccine or other adjuvants (see Tumor Immunology: Nonspecific Immunotherapy) to induce an enhanced immune response against the tumor. Prolonged remissions or improved reinduction rates have been reported in some series but not in most.
Defined tumor antigen–based vaccines are among the most promising approaches in cancer immunotherapy. An increasing number of tumor antigens have been unequivocally identified as the target of specific T cells grown from cancer patients.
Cellular immunity (involving cytotoxic T cells) to specific, very well defined antigens can be induced. Defined TAAs can be delivered into patients either in the form of peptides (usually co-administered with immunogenic adjuvants) or DNA that encodes specific protein (via recombinant viruses).
Recent studies have shown that the most potent responses can be achieved if TAAs are delivered using antigen-presenting cells (dendritic cells). These cells are obtained from the patient, loaded with the desired TAA, and then reintroduced intradermally to stimulate the endogenous T cell to respond to the specific antigen. Further, these cells can be genetically modified to secrete additional immune-response stimulants.
Another treatment method combines antigen-presenting cells and tumor cells in an attempt to utilize the entire spectrum of potential TAAs. Dendritic cells are either loaded with tumor cell lysates or dying tumor cells or are fused with living tumor cells. These methods are in clinical trials.
Nonspecific
Immunotherapy
Interferons (IFN-α, -β, -γ) are glycoproteins that have antitumor and antiviral activity. Depending on dose, interferons may either enhance or decrease cellular and humoral immune functions. Interferons also inhibit division and certain synthetic processes in a variety of cells. Human clinical trials have indicated that interferons have antitumor activity in various neoplastic processes, including hairy cell leukemia, chronic myelocytic leukemia, AIDS-associated Kaposi's sarcoma, non-Hodgkin lymphoma, multiple myeloma, and ovarian carcinoma. However, interferons are associated with significant adverse effects, such as fever, malaise, leukopenia, alopecia, and myalgias.
Certain bacterial adjuvants (BCG and derivatives, killed suspensions of Corynebacterium parvum) have tumoricidal properties. They have been used with or without added tumor antigen to treat a wide variety of cancers, usually along with intensive chemotherapy or radiation therapy. For example, direct injection of BCG into neoplastic tissues has resulted in regression of melanoma and prolongation of disease-free intervals in superficial bladder carcinomas and may help prolong drug-induced remission in acute myeloblastic leukemia, ovarian carcinoma, and non-Hodgkin lymphoma.
Last full review/revision November 2005
Content last modified November 2005
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