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Abstract
Immunotherapy may be the next great hope for cancer treatment. While monoclonal antibodies, cytokines, and vaccines have individually shown some promise, it is likely that our best strategy to combat cancer will be, to attack on all fronts. Clearly, different strategies demonstrate benefit in different patient populations. It may be that the best results are obtained with vaccines in combination with a variety of antigens, or vaccine and antibody combinations. Nonspecific and specific immunotherapy combinations may be another potent strategy. The effect of any of the forementioned strategies in combination with more traditional cancer therapies is another avenue, as we have seen some benefit in terms of duration with cytokines and chemotherapy.
Through these concerted efforts, our ultimate achievable goal may be a durable anti-tumor immune response that can be maintained over the course of a patient’s lifespan.
Given the long history of tumor immunology-marked by recurrent cycles of high expectations and disappointments-we need to exert considerable caution in making any predictions. But many promising opportunities wait to be studied, and they give us reason to expect that powerful immunologic therapies will one day become a reality.
Perhaps these therapies will yield cures-the universal objective of cancer researchers, health care providers and, of course, patients. A more achievable aim, though, may be developing therapies that can change the nature of cancer from a progressive and lethal disease to one that can be controlled throughout a long life. That result would be less than ideal, but it could make a world of difference for many afflicted with tumors not readily treatable today.
The discipline of tumor immunology, once limited to a basic
understanding of the immune system under normal and pathologic
conditions, has evolved to include potential clinical applications
toward the immunotherapy of malignancy. In turn, tumor
immunotherapy has emerged from the underlying concept that the
immune system may be appropriately manipulated or modulated
against neoplastic disease or the neoplastic process.
For immunotherapy to be effective, however, it must satisfy the following major premises:
(1) the host immune system is competent and contains the
relevant precursor cells and functional APC populations.
(2) tumor cells are “antigenic” (i.e., they express antigens that selectively or specifically distinguish them from normal host tissues for effective immune recognition and attack).
(3) under conditions of peripheral T-cell anergy, such immunotherapeutic strategies must be able to overcome or “break” potential “tolerance” mechanisms, without inducing unacceptable autoimmune toxicities.
Indeed, in human cancer, a plethora of tumor antigens have now
been defined and characterized. Generally classified as TSAs or
TAAs, these antigens have been discussed in detail here. TSAs represent the expression of altered self-proteins as a consequence of viral transformation or genetic mutations. Such aberrant proteins (e.g., those found in HPV, point-mutated ras or mutated p53-associated malignancies) have been shown to contain unique antigenic determinants, thereby making such “neoepitopes” potentially attractive targets for cancer immunotherapy.
TAAs represent the overexpression of normal self-proteins—such as oncofetal, differentiation, or nuclear antigens—and include, for example, Her-2/neu, CEA, a variety of Melanoma-associated antigens (e.g., MAGE, MART-1, gp100, and tyrosinase) and wild-type p53, respectively.
Although TAAs may not be considered foreign moieties because of their overexpression in many human cancers, peptide sequences derived from those proteins have been shown to serve as selective targets for immune recognition in both normal and tumor-bearing patients.
A potentially important difference between TSAs and TAAs may reside in the initiation phase of the immune response. Thus, the development of animal models has provided a preclinical in vivo environment to address (1) general safety and toxicity issues; (2) certain biologic and mechanistic principles, with implications for understanding fundamental requirements important for the effective induction of cell mediated immunity in human neoplasia; and (3) the design of appropriate therapeutic modalities, including both active- and passive-based regimens for cancer immunotherapy.
Rapid achievements in the areas of molecular biology and immunology have led to the development of recombinant vaccines encoding TSAs, TAAs, or cytokines in monovalent and polyvalent constructs for use in active immunotherapy.
Genetic modification of both the variant and constant regions of Ig molecules has increased the interest in the clinical use of monoclonal antibodies (mAbs) with improved binding and metabolic characteristics, as well as enhanced effector functions.
Moreover, unraveling the basic mechanisms of antigen recognition, antigen processing, antigen presentation, and tumor escape processes has led to the identification and exploitation of dendritic cells (DCs), costimulatory molecules, and antigen-specific T cells for use in diverse aspects of immunotherapy.
While considerable knowledge has been acquired to this point, the steady influx of new information, may well further translate the science of tumor immunology and immunotherapy into clinical modalities for a range of urological malignancies and, perhaps, strategies for the prevention of certain neoplasms.