Immunotherapeutic strategies (1)
tumor immunology
A. Enhancement of Nonspecific Immunity
Around the end of the 19th century. the American surgeon William Coley began to inject cancer patients with tumor cell lysates that were contaminated with bacteria clue to the lack of sterile preparation techniques.
Surprisingly. some tumor regression was observed. Later in the 20th century. tumor vaccination was tested again. but the use of unmodified tumor cells alone did not induce significant responses. Adjuvants were soon added in attempts to en hance the tumor specific immune response. At tenuated mycobacterial strains. such as bacillus Calmette Guérin (ECG) or Corynebacterium parvum. were primarily used.
The Newcastle disease virus has also been used in more recent experiments. Some clinical studies based on this strategy are still in process. Although no sweeping successes can be expected from these trials, some positive results indicate that improved vaccination methods might be success fully developed in the future. In the past 3-4 years, tumor cells have been modified by gene transfer to selectively induce T cell mediated immune responses. The goal is to stimulate the local growth ochells or dendritic cells by the secretion of cytokines. such as [L 2, IL 4. IL 7. and GM CSF. in the hope of activating tumor specific T cells.
Cytokines can also be administered systemically. However, only interferon u (lFN u) and IL 2 have become established in a few types of tumors (2). In addition to its immunostimulatory effect. lFN u also has a direct antiproliferative effect that may be responsible for some of the therapeutic effects. Renal cell carcinomas and malignant melanomas appear to respond better than other tumors to immunotherapeutic regimens. but the reason for this is still unknown.
Tumor necrosis factor a (TNF u) is also used in patients with sarcomas and melanomas in limb perfusion together with antineoplastic drugs to enhance tumor cell damage.
B. Induction of a Specific T Cell Response
In many patients, surgical excision can success fully eliminate the primary tumor at the time of diagnosis. However. a proportion of these patients will later develop distant metastases or local recurrences. This is why adjuvant therapy is performed in patients with certain risk factors (tumor type. degree of malignancy, depth of tumor invasion. lymph node involvement. etc).
Nonetheless. in most cases. it still is not possible to induce a specific T cell response to the tumor by administering irradiated autologous tumor cells or tumor cell lysates (1). Even under ideal conditions where the tumor cells present tumor antigen to the T cells, a sufficient antitumor immune response is not ob served because the tumor cells lack the required costimulatory molecules, such as B7 (CD80/86). A number of trials is being performed in which tumor cells are genetically modified to express the B7 anti gen in order to increase their immunogenicity (2)
. Another way to induce an immune response to poorly immunogenic tumor cells is to allow professional antigen presenting cells (APC) to present the tumor antigens (3). The professional APCs express all important stimulatory molecules needed to induce an effective T cell response. Accordingly, dendritic cells generated exvivo can therefore be loaded (pulsed) with tumor cell lysates, purified tumor antigens. or specific tumor peptides.
The results of preliminary clinical trials are promising. The local instillation of Calmette Guérin bacillus after local resection of carcinoma of the bladder is a special form of immunotherapy. BCG treatment prevents the development of recurrences in a high percentage of cases. Instillation of the bacillus may trigger inflammatory processes in which activated antigen presenting cells are able to capture antigens from remaining tumor cells and effectively present them to the immune system.
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