Cancer Therapy Vol 1, page 359
Figure 4. VH gene family usage of combined patient data differs significantly from the expected frequencies and from normal PBL (p=0.000015 & <0.0001 respectively). (reproduced with permission, from Nzula et al, Cancer Research 63:3275-80, 2003)
Accumulation of p53 protein, owing to mutations in the p53 gene, is a common event in breast, lung, cervical, colon and gastric carcinomas (Gasco et al, 2003). Accumulation of mutated p53 can trigger the humoral immune response and p53 antibodies have been detected in the sera of patients with different types of tumours (Soussi, 2000). These antibodies can also recognise the native form of p53 (Labrecque et al, 1993). Anti-p53 antibodies can indicate breast cancer relapse (Regele et al, 2003). In a retrospective study of 24 breast cancer patients, Regele et al reported a decrease in p53 antibodies that paralleled therapy in 64% of the patients. In 18% of patients, relapse was preceded by an increase of the antibody titre. Thus, monitoring serum levels of p53 antibodies could provide essential information about the clinical course of the disease. Expression of p53 is correlated with resistance to paclitaxel, an important agent in the pharmacological treatment of metastatic breast cancer (Schmidt et al, 2003). A study of 33 patients with metastatic breast cancer found that none of the tumours with p53 expression responded to paclitaxel. In contrast, all of the patients without p53 expression responded to treatment. Thus, p53 expression could be used to identify paclitaxel-resistant patients prior to using ineffective therapy with major side effects.
Mehren et al, 2000; Greiner et al, 2002). In addition, Phase I clinical trials of a recombinant vaccinia virus-CEA vaccine in metastatic colorectal, breast and lung cancer patients showed enhancement of immune responses with no toxicity (McAneny et al, 1996; Schlom et al, 1996). Consequently, CEA represents another potential target for recombinant vaccines against different types of cancers including breast.
E. Antibody-mediated tumour cell killing mechanisms There are several mechanisms through which antibodies bound to tumour antigens can induce tumour cell death. The main mechanism is called antibodydependent cell-mediated cytotoxicity (ADCC), in which antibodies bound to tumour cells activate effector cells of the immune system. Receptors expressed on natural killer cells and other leucocytes bind to the antibody-tumour cell complex through the antibody Fc region, release cytotoxic granules containg perforin and granzymes and destroy the tumour cell (Velders et al, 1998; Snijdewint et al, 2001). Antibody binding to tumour antigens can also trigger the classical complement cascade, leading to complementmediated cell lysis (Livingston et al, 1997). When the first component of complement, C1q, binds to the Fc portion of the antibody-tumour cell complex, this stimulates binding and activation of the remaining components of the complement system (C1-C9) at the cell surface. The activation of complement results in the release of anaphylatoxic and chemotactic factors (C3a, C5a) and the formation of the membrane attack complex (C5b-C9), which initiates lysis of the tumour cell membrane.
D. Carcinoembryonic antigen Human carcinoembryonic antigen (CEA) is a glycoprotein normally expressed in colon epithelium and some fetal tissues. CEA is over-expressed on approximately 50% of breast cancers and carcinomas of the colon, pancreas, lung and gastrointestinal tract (Marshall, 2003). Despite the poor immunogenicity of endogenous CEA, recent recombinant vaccine strategies have demonstrated cellular and humoral immune responses that recognise CEA and kill tumour cells (von
V. Conclusions The function and prognostic significance of tumourinfiltrating lymphocytes has been controversial for over 50 359