Antigens tumor associated

The active immunotherapeutic approach is specific and based on the premise that tumor antigens are immunogenic and the host is sufficientiy immunocompetent to mount an effective immune response to an autologous tumor. Theoretically, a weak or suppressed host immune system that had allowed the formation of a tumor may be overridden by active immunization or immunostimulation. In practice, vaccines composed of so-called autologous tumor extracts have been used to treat patients with malignant melanoma (73), and purified melanoma tumor-associated antigens have been used to ehcit antibody responses in melanoma patients (74). 

Besides the hormone therapy, the notion of targeted cancer therapy is not so new and can be traced back to the 1940 s [2]. Early approaches included the largely unsuccessful use of antibodies, often conjugated with radioisotopes or toxins, directed against tumor-associated antigens. 

Bladder tumor-associated antigen (BTA), a human complement factor H, is produced by bladder cancer cells (men two to three times as often as women). Cancer cells are sometimes seen in urine samples by microscope cytoscopy (examination of the bladder with an instrument inserted into the urethra), which can reveal abnormal areas. Biopsy is needed to confirm the diagnosis. Early stage cancer confined to the bladder wall can often be removed with a cytoscope. If several tumors are present, they are removed by infusing the bladder with a solution containing bacteria able to stimulate the immune system. 

The most common BTA test is an immunoassay-based assay that uses monoclonal antibodies to detect the presence of bladder tumor-associated antigen in urine. In clinical studies, the BTA test was compared with cytoscopy-voided urine for the detection of recurrent bladder cancer. The sensitivity of BTA appeared su-... 

Comparison between Bladder Tumor-Associated Antigen (BTA) and Cytology... 

Gion, M Mione, R Nascinben, O., et al. The tumor-associated antigen CA15-3 in primary breast cancer. Br. J. Cancer 63,809-813 (1991). 

Sarosdy, M. F., deVere, R. W Soloway, M. S. Sensitivity of bladder tumor-associated antigen compared to cytology. J. Urol. 154, 379-384 (1995). 

Solbrig CM, Saucier-Sawyer JK, Cody V et al (2007) Polymer nanoparticles for immunotherapy from encapsulated tumor-associated antigens and whole tumor cells. Mol Pharm 4 47-57... 

Alam, F., Soloway, A.H., Barth, R.F., Mafune, N., Adams, D.M., and Knoth, W.H. (1989) Boron neutron capture therapy Linkage of a boronated macromolecule to monoclonal antibodies directed against tumor-associated antigens./. Med. Chem. 32, 2326-2330. 

Fujiwara, K., Matsumoto, N., Yagisawa, S., Tanimori, H., Kitagawa, T., Hirota, M., Hiratani, K., Fukushima, K., Tomonaga, A., Hara, K., and Yamamoto, K. (1988) Sandwich enzyme immunoassay of tumor-associated antigen sialosylated Lewisx using b-D-galactosidase coupled to a monoclonal antibody of IgM isotype./. Immunol. Meth. 112, 77-83. 

Clinically, monoclonal antibodies are also proposed as drug delivery vehicles in certain tumors where specific tumor-associated antigens are expressed. In this context, investigators have found that by conjugating toxins such as the A chain polypeptide of the plant protein ricin or the bacterial toxin from Corynebacterium diphtheriae to monoclonal antibodies specific for certain tumor type, as few as one or two molecules of antibody-toxin conjugate can destroy a tumor cell in vitro. Some success has also been obtained in clinical trials with monoclonal antibody-toxin conjugates. 

Scheme 10.3 Preparation of the tumor-associated antigen globo-H by a two-direction...

The mode of association of peptides to liposome carriers might also be critical to induce a preferential immune response either humoral or cell mediated. For example, using a human mucin MUCl 20-mer peptide, it was found that only the physical association of the peptide to liposomes (either encapsulated or surface exposed after anchoring) was necessary to observe a cell-mediated response (34). In line with this observation, it was recently shown that a soluble peptide, representing a Melan-A/MART-1 tumor-associated antigen, when encapsulated into sterically stabilized liposomes, was able to stimulate a CTL response and this construct represented a suitable formulation for a specific tumor immunotherapy (69). In contrast, and in agreement with other studies (16), only the liposome surface exposed... 

Figure 6 Immunopotentiating reconstituted influenza virosomes (IRIV) adjuvant effects in the induction of tumor associated antigen-specific cytotoxic T cell. CD14-negative cells from a healthy donor peripheral blood mononuclear cells were cocultured with autologous immature dendritic cells (iDC) in the presence of Melan-A/Mart-l27-35, alone (A) or supplemented with either control liposomes (B) or IRIV (1 50, C). On day 7, culture cells were restimulated with Melan-A/MART-127-35 pulsed iDC and cultured for six further days [see Materials and Methods ]. On day 7 after restimulation cells were stained with fluorescein isothiocyanate-conjugated anti-CD8 and phosphatidylethanolamine-conjugated HL A-A0201 /Melan-A/MART -127-3 5 tetramers. Source From Ref. 6.

In addition to having an overabundance of several self-antigens, tumor cells express unique antigens, which can be recognized by the host immune system, provided that the immune system is simultaneously activated. Without this activation, the immune system will become tolerized to the unique antigens known as tumor-associated antigens (TAAs), which are usually small peptides of 8 to 10 amino acids. The potential exists for the eradication of cancers by injection of TAAs and the subsequent immune response. Indeed, there have been many tumor-reactive CTLs identified that recognize specific TAAs (15). 

R.H. Vonderheide, W.C. Hahn, J.L. Schuitze, and L.M. Nadier, The telomerase catal34ic subunit is a wideiy expressed tumor associated antigen recognized by cytotoxic T lymphocytes. Immunity 10, 673-679 (1999). 

The conjugation of deacetylvinblastine to a monoclonal antibody that recognizes a tumor-associated antigen results in an agent with substantial antitumor activity in mice with relatively little toxicity (la). Conjugates of this type are of obvious interest for future clinical trials as site-directed cancer chemotherapeutic agents. 

Figure 8.3. Schematic representation of bispecific antobody mediated tumor cell recognition by an immune effector cell. Summarised are effector cell types, trigger molecules and tumor associated antigens used as a targed as reported in the literature. From reference [37].

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