Prior to the identification of specific human tumour antigens, many clinical trials were performed attempting to immunise cancer patients against either whole cancer cells or subcellular fractions from cancer cells. The identification of genes encoding tumour antigens, however, has made it possible to develop specific immunotherapies based on attacking tumour cells bearing the identified antigens. A variety of clinical approaches utilising these genes or gene products are possible as summarised in the following table.
Active immunotherapy (“Cancer vaccines”)1.Immunisation with:i)purified antigenii)immunodominant peptide (native or modified)iii)“naked” DNA encoding the antigeniv)recombinant viruses encoding the antigenv)antigen presenting cells pulsed with protein or peptide (or transfectedwith genes encoding the antigen)2.Use of cytokine adjuvants such as IL-2 and IL-12 administeredsystemically or encoded by the immunising vectorPassive immunotherapy (“Adoptive immunotherapy”)1.Transfer of cells sensitized in vitro to the specific antigen (bulk orcloned populations)2.Transduction of effector cells (or stem cells) with genes encoding Tcell receptors that recognise sepcific antigens.
Immunisation with intact protein has the potential advantage of simultaneously immunising against both class I and class II epitopes but requires extensive and time-consuming efforts to purify large amounts of tumour antigen. The identification of class I and class II peptide within a tumour antigen makes it possible to immunise with high levels of pure synthetic peptide. The peptide approach also has the advantage that one can choose between a class I and a class II type response (or mixture) by choosing which epitopes to use. Immunisation with peptide also means that subdominant and/or cryptic epitopes can be chosen (as the need for antigen processing may be bypassed or reduced to a “trimming role) in order to stimulate a different subset of T cells. Also the peptide may be modified (for example at their HLA class I or II anchor sites) to increase their immunogenicity.
In the past few years, much attention has been given to the role of CD8+ T cells in tumour immunity. Tumour-specific CD8+ CTLs have been shown to be capable of lysing tumour cells directly and eradicating tumour masses in vivo in animal models. However, CD4+ T cells are also thought to play a critical role (Wang and Rosenberg (1999) Immunological Reviews 170:85-100) and it may be that optimal cancer vaccines require the participation of both CD4+ and CD8+ T cells.
A number of oncofoetal or tumour-associated antigens (TAAs) have been identified and characterised in human and animal tumours. In general, TAAs are antigens expressed during foetal development which are downregulated in adult cells, and are thus normally absent or present only at very low levels in adults. Tumour cells have been observed to resume expression of TAAs, and the application of TAAs for tumour diagnosis, targeting and immunotherapy has therefore been suggested.
The TAA 5T4 (see WO 89/07947) has been previously characterised. It is a 72kDa glycoprotein expressed widely in carcinomas, but having a highly restricted expression pattern in normal adult tissues (see Table 1). It appears to be strongly correlated to metastasis in colorectal and gastric cancer. The full nucleic acid sequence of human 5T4 is known (Myers et al., 1994 J Biol Chem 169: 9319-24).
TABLE 1Distribution of Human 5T4Tumour5T4 FrequencyType(%)Breast84Ovarian71Gastric74Colorectal85
(Starzynska et al., Eur J Gastroenterol Hepatol 1998 June;10(6):479-84; Starzynska et al., Br J Cancer 1994 May;69(5):899-902; Starzynska et al., Br J Cancer 1992 November;66(5):867-9)
5T4 has been proposed as a marker, with possible mechanistic involvement, for tumour progression and metastasis potential (Carsberg et al., (1996) Int J Cancer 1996 Sep. 27;68(1):84-92). 5T4 has also been proposed for use as an immunotherapeutic agent (see WO 00/29428).
USPTO Backgrounds
USPTO Backgrounds