Tumourassociated antigens

In this text, the term 'tumour-associated antigen' represents any antigen associated with any cancer cell, no matter what factor(s) originally prompted cellular transformation. (In some circles, the term 'tumour-associated antigen' is often applied more specifically: to antigens associated with virally transformed cells.) Identification of tumour-associated antigens forms a core requirement for effective tumour immunotherapy. Identification of such tumour-associated antigens remains a very active area of biomedical research. From the limited data generated to date, tumour-associated antigens can generally be categorized into one of three groups (Table 13.3).

Many tumour types are induced by chemical and/or physical carcinogens we encounter in our living/working environments. Most of these tumours are initiated when the carcinogen induces a point mutation in a nucleotide sequence, thus perhaps altering expression levels of the gene product or altering its functional characteristics. Because such mutations are random, it is not surprising that each resulting tumour displays its own unique tumour-associated antigen(s). This renders an immunological approach to detection/therapy impractical in such instances, as the specific tumour-associated antigens unique to that case would first have to be identified.

In contrast to the above situation, cancers induced by viruses generally exhibit immunologi-cal cross-reactivity. Any specific virus will often induce expression of the same tumour antigen no matter what cell type it transforms. Moreover, in some cases, different transforming viruses can induce production of the same tumour antigen(s). Immunodetection/immunotherapy of such cancers is thus rendered attractive. Once a tumour antigen is identified, antibodies raised against it will likely cross-react with several other tumour types.

DNA viruses, such as adenoviruses and papovaviruses (e.g. polyoma and SV40), induce cellular transformation in rodents. Other viruses have been implicated in human cancers. Epstein-Barr virus, for example, has been implicated with nasopharyngeal carcinoma, P-cell lymphomas and Hodgkin's lymphoma. Human papilloma virus is linked to most cervical cancers.

Certain RNA viruses, particularly retroviruses, have also proven capable of inducing cancer. Retroviruses known to induce cancer in animals include Rous sarcoma virus, Kirsten murine

Table 13.3 Characterizing of tumour-associated antigens. Antigens commonly expressed by a number of different tumour types render practical application of tumour immunodetection/immunotherapy in those cases

Cellular-transforming factors

Tumours induced by chemical carcinogens/irradiation Virally induced tumours

Various induction factors (often unknown)

Associated tumour antigen

Each tumour usually displays distinct antigen specificity Various tumour types display identical tumour-associated antigens (especially if tumours are induced by the same virus) The same oncofoetal antigen can be expressed by a number of different tumour types sarcoma virus, avian myelocytomatosis virus, and various murine leukaemia viruses. Thus far, the only well-characterized human RNA transforming virus is that of human T-cell lymphotropic virus-1 (HTLV-1), which can induce adult T-cell leukaemia/lymphoma. The identification of antigens uniquely associated with various tumour types and the identification of additional cancer-causing viruses remain areas of very active research.

Another group of antigens associated with some tumour types are oncofoetal antigens. These antigens are proteins that are normally expressed during certain stages of foetal development. Subsequent repression of their structural genes, however, prevents their expression at later stages of development and/or into adulthood. Characteristic of some cancers is the re-expression of oncofoetal antigens. Some such antigens remain attached to the cancer cell surface, whereas others are secreted in soluble form. Although these oncofoetal proteins are not recognized as foreign by the host's own immune system, they do represent important potential diagnostic markers. Although some such markers have been identified, efforts continue to identify additional members of this family.

CEA and a-fetoprotein (AFP) represent the most extensively characterized oncofoetal antigens thus far. We have already encountered CEA in the guise of its use as a marker for cancers of the colon and rectum. CEA is a 180 kDa integral membrane glycoprotein. It also may be secreted into the blood in soluble form. It is expressed mainly in the gut, liver and pancreas, during the first 6 months of foetal development. However, it is now known to be expressed (although at greatly reduced levels) by adult colonic mucosal cells and in the lactating breast. Elevated levels of either soluble (serum) or cell-bound CEA are normally indicative of cancers of the gastrointestinal tract.

AFP is a 70 kDa glycoprotein found in the circulatory system of the developing foetus. It is synthesized primarily by the yolk sac and (foetal) liver. AFP is present only in vanishing low quantities in the serum of adults (where it is replaced by serum albumin). Elevated adult serum levels of this marker are often associated with various cancers of the liver, as well as germ cell tumours. It is also sometimes expressed by gastric and pancreatic cancer cells. Although a useful tumour marker, increased serum AFP levels also often accompany cirrhosis and some other non-cancerous liver diseases.

CA125 represents an oncofoetal protein that is expressed by up to 90 per cent of ovarian adeno-carcinomas. Some of the protein is released from the tumour site into the general circulation. Elevated serum CA125 levels, therefore, have some diagnostic value. Imaging of actual tumour sites can also be undertaken using radiolabelled antibody coupled to immunoscintigraphy. Indimacis-125 is the trade name given to such a product approved in 1996 for use in the EU. The product is an mIn-labelled F(ab)2 fragment derived from a murine hybridoma cell line. Although some of the product is likely absorbed by the circulatory form of the oncofoetal protein, the product has proven effective in imaging relapsing ovarian adenocarcinoma.

In summary, TSA-based complications in the context of developing antibody-based cancer therapies include:

• Limited numbers of TSAs currently characterized.

• Some cancer types, depending upon their cause, may display unique TSAs in different patients.

• TSAs are often expressed, albeit at lower levels, by one or more additional (non-transformed)

body cell types.

• In some instances, binding of antibody results in immediate shedding of Ab-TSA from the cell surface.

• TSA expression can be transitory. For many tumours, only a proportion (albeit a large one) of the tumour cells express TSAs at any given time.

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