c-erbB-2 as a target for immunotherapy.
The c-erbB-2 proto-oncogene encodes a 185 kDa transmembrane Type 1 tyrosine kinase receptor whose amplification and/or overexpression has been linked with poor prognosis in a variety of cancers. The oncoprotein has been suggested to play a key role in tumour cell invasion, motility and metastasis, and in responsiveness to therapeutic agents. Over-expression of c-erbB-2 therefore identifies an important subset of patients with a high probability of relapse, but low probability of response to certain conventional therapies. The cell surface location of the oncoprotein, its stability of expression and low levels in normal adult tissues render it an attractive target for immunotherapeutic intervention. Although a 'self' antigen, there is evidence that c-erbB-2 p185 can induce both humoral and cell-mediated immune responses in cancer patients. Approaches to exploit p185 as an immunotherapeutic target include vaccination with peptides, plasmid DNA or vectors (viruses/bacteria) carrying the gene; with cytokines, co-stimulatory factors and superantigens being evaluated as adjuvants. Many monoclonal antibody (mAb)-based strategies are also in clinical development. Monoclonal antibodies can serve multiple functions; direct inhibition of c-erbB-2 activity, recruitment of host effector mechanisms and direct or indirect delivery of toxic payloads. Clinical trials in patients with late stage disease have shown that many of these approaches are safe, feasible and relatively non-toxic, and, in some cases, objective responses have been seen. As with all immunotherapy, the greatest benefit is likely to be obtained in patients with minimal residual disease in an adjuvant setting; such studies are awaited with interest.
Section of Cancer Therapeutics, McElwain Laboratories, Institute of Cancer Research, Cotswold Rd., Belmont, Sutton, Surrey, SM2 5NG, UK.
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