Both experimental and naturally occurring tumors are capable of stimulating a specific antitumor immune response. This observation suggests that there are foreign proteins (antigens) on tumor cells that classically have been described as resulting in humoral and cellular immune responses. However, experimental models suggest that a T-cell (cell-mediated) response may be more important in the killing of tumor cells than a B-cell (humoral) response.

A detailed description of the components of the immune system is beyond the scope of this chapter, but certain features of the immune system as they pertain to diagnostic and therapeutic issues will be reviewed.

Tumor antigens can be divided into tumor-specific antigens and tumor-associated antigens. Tumor-specific antigens are not found on normal tissue, and they permit the host to recognize a tumor as foreign. Tumor-specific antigens have been shown to exist in oncogenesis models utilizing chemical, physical, and viral carcinogens but appear to be less common in models of spontaneous tumor development.

The identification of tumor-specific antigens led to the theory of immune surveillance, which suggests that the immune system is continuously trolling for foreign (tumor-specific) antigens. This theory is supported by the observation that at least some cancers are more common in immune-suppressed patients such as transplant patients or human immunodeficiency virus–infected individuals. However, many cancers are not overrepresented in these patient populations. Furthermore, spontaneous tumor models, which more closely resemble human carcinogenesis, appear to have a less extensive repertoire of tumor-specific antigens but instead have been found to express many tumor-associated antigens.

Tumor-associated antigens are found in normal cells but either become less prevalent in normal tissue after embryogenesis (eg, alpha-fetoprotein [AFP]) or remain present in normal tissue but are overexpressed in cancer cells (eg, prostate-specific antigen [PSA]). In either case, the more ubiquitous nature of these antigens appears to cause reduced immune reactivity (also known as tolerance) to the specific antigen. The mechanisms of tolerance are complex and may be due in part to the absence of other required costimulatory molecules (such as B7, a molecule required for T-cell stimulation). Recent evidence has also implicated a number of immune checkpoints that result in downregulation of the cellular immune response. In particular, two molecules, CTLA-4 and PD-1, have been identified on activated lymphocytes that dampen the immune response, and therefore have been exploited as potential therapeutic targets.

The development of monoclonal technology has allowed the development of many antibodies against many tumor-associated antigens and has provided insight into the regulation and expression of these antigens. The reexpression or upregulation of these tumor-associated antigens during carcinogenesis may lead to immune response (or loss of tolerance). Many novel therapeutic approaches have sought to break this tolerance, and approaches to enhance a patient’s immune response will be discussed.

Humoral Immunity

A large number of monoclonal antibodies have been developed against a variety of tumor-associated antigens. Oncofetal antigens such as AFP and beta-human chorionic gonadotropin (β-hCG) are important markers in germ cell tumors. β-hCG is also expressed in a small percentage of patients with bladder carcinoma. Antibodies directed against specific targets such as vascular endothelial growth factor (VEGF) have been developed and have been tested for the treatment of advanced prostate cancer, renal cell carcinoma (RCC), and transitional cell carcinoma (TCC).

Antibodies in Cancer Diagnosis and Detection

Prostate Cancer

Immunoassays are used to test both body fluids and tissues for the presence of tumor-associated antigens. In the urologic cancers, the most obvious example is the development of monoclonal antibodies against PSA. The utility and limitations of PSA are described elsewhere in this volume. Other antigens that have been tested in prostate cancer include prostatic acid phosphatase, which has largely been replaced by PSA in screening programs and in patients with low tumor burden. Prostatic acid phosphatase may be of some use in detecting or following bone metastases and as a predictive marker of response to therapy for metastatic disease. Antibodies to prostate-specific membrane antigen (PSMA) have been used, primarily for immunohistochemistry.

Renal Cell Carcinoma

Unfortunately, there are as yet no well-established antigens (or antibodies) that can be used to reliably evaluate and monitor RCC, although a variety of target antigens are being evaluated.

Bladder Cancer

Two oncofetal antigens, β-hCG and carcinoembryonic antigen, are expressed by a minority (≤20%) of TCCs. These markers are not routinely used, but in diagnostic dilemmas, measurement of serum levels of β-hCG or staining of tissue for this antigen may be useful.

Germ Cell Tumors

As described in Chapter 23, antibodies to hCG and AFP are routinely used to detect shed antigens from germ cell tumors in the bloodstream. These antigens can also be detected in tissue samples. While the use of serum markers in germ cell tumors is reviewed elsewhere, it is worth noting that the presence of the oncofetoprotein AFP, either in serum or in tissue specimens, is pathognomonic for a nonseminomatous germ cell tumor, regardless of results of routine pathologic evaluation. In addition to their diagnostic utility, AFP and hCG can be used as markers of response to therapy and as predictive factors of outcome. For example, the international germ cell tumor risk classification schema for patients with metastatic disease relies heavily on AFP and hCG levels as well as levels of a nonspecific marker, lactate dehydrogenase, to assign patients with nonseminomatous germ cell tumors to one of three risk levels (see Chapter 23).

Radioimmunodetection

Monoclonal antibodies to a specific antigen can be radiolabeled, and the preferential binding of the monoclonal antibody to tumor cells can be exploited. Theoretically, such an approach could be used for the presurgical evaluation of disease, postsurgical evaluation for minimal residual disease, confirmation of cancer identified by other imaging modalities, and detection of recurrent disease. There are several potential impediments to successful tumor radioimmunodetection. These include dilution of antibody in the bloodstream; metabolism of the antibody; nonspecific binding in liver, reticuloendothelial system, bone marrow, and elsewhere; binding of antibody by circulating or shed antigen; and the development of neutralizing human antimouse antibodies.

The only radioimmunodetection system for urologic cancers at this time is 111In-capromab pendetide (Prostascint), a murine monoclonal antibody to PSMA. Its use has been hampered by a fairly laborious administration process, operator dependence in interpretation of scans, and a less than satisfactory positive predictive value. The use of 111In-capromab pendetide is described in Chapter 10.

Immunotherapy with Monoclonal Antibodies

Immunotherapy with monoclonal antibodies alone (“naked antibodies”) has been fairly extensively evaluated. The use of monoclonal antibodies against tumor-associated antigens has met with only limited success in patients with solid tumors including prostate and kidney cancer. In lymphoproliferative disorders such as leukemia and lymphoma, some antibodies to tumor-associated surface antigens appear to result in tumor cell death. The mechanism for these effects is certainly multifactorial but may, in part, be mediated by resultant complement fixation.