Antitumor vaccines

Dendrimers, dendrons and other dendritic systems have been synthesized as interesting compounds with a great potential in different biomedical applications, including delivery carriers of drugs, development of synthetic vaccines, antitumor systems or as therapeutic agents per se with, for example, antiviral and antibacterial properties. 

The two examples from our work we are going to describe below are the design and study of liposomal diepitope constructs combining either (i) B and T-helper (Th) peptide epitopes, which induced particularly powerful humoral responses (21) (Fig. 3) or (ii) CTL and Th epitopes, which provided a powerful antitumor vaccine (74) (Fig. 4). For the production of these constructs we have conjugated peptides that contain a cysteine residue either at the N- or C-terminus, to the surface of preformed liposomes by reaction with thiol reactive functionalized phospholipids and/or PamaCys lipopeptide anchors (Fig. 2). To that end, we have developed strategies that give, in aqueous media, high... 

Roth A, et al. Induction of effective and antigen-specific antitumor immunity by a liposomal ErbB2/HER2 peptide-based vaccination construct. Br J Cancer. In press. 

Development of a Liposomal Vaccination System for Immunity-Modulating Antitumor Therapy... 

The prophylactic antitumor efficiency was tested by injecting 12 mice twice in seven days with AVE 3 TRP-2 (10 pg TRP-2) and AVE 3 1826 CpG (1.3 pg CpG) intradermally the control group remained untreated. Seven days after the last immunization 2 x 10 B16 tumor cells in 200 pL HBSS were injected into the tail vein of each mouse. Twenty days after tumor inoculation, the animals were sacrificed and the metastases in the prepared lungs counted. As Table 2 shows, the liposomal vaccination has a significant effect on the tumor growth in comparison to untreated animals. This is also reflected by the visual appearance of the lungs (data not shown). 

To review, in an experimental mouse model, LPDI/E7 vaccination both prevents the establishment of metastatic E7-expressing tumors in naive mice through an induced E7-specific T-cell immune response and, in mice with previously established E7-expressing tumors, causes tumor regression with one subcutaneous injection of LPDI/E7 [Han SJ, et al. Subcutaneous antigen loading of dendritic cells by liposome-protamine-DNA (LPD) nanoparticles results in their activation and induction of specific antitumor immune response (impublished)]. A robust immune response follows administration of LPDI/ peptide particles, which can be used as either a preventative or therapeutic cancer vaccination strategy due to the ability of the particles to prevent and eliminate tumors, respectively, in mouse models. 

Cytokines have been under clinical investigation as adjuvants to vaccines, and IFNs and IL-2 have shown some positive effects in the response of human subjects to hepatitis vaccine. IL-12 and GM-CSF have also shown adjuvant effects with vaccines. GM-CSF is of particular interest because it promotes recruitment of professional antigen-presenting cells such as the dendritic cells required for priming naive antigen-specific T-lymphocyte responses. There are some claims that GM-CSF can itself stimulate an antitumor immune response, resulting in tumor regression in melanoma and prostate cancer. 

The phase I and phase II trials of therapeutic vaccines (Table 3.) show a weak toxicity of lipids A, furthermore they show a stimulation of the acquired antitumoral immune response. CTL responses correlate better than antibody responses to clinical outcomes, in agreement with current concepts of antitumor immunity. Phase m trials are now necessary to determine the effective protocol. 

The overexpression of HER-2 protein in cancer cells makes it an ideal target for vaccines and other targeting strategies. Vaccines optimized to induce maximum T cell immunity to HER-2 may lead to potent in vivo antitumor immunity. HER-2 protein has been evaluated as a potential target for the development of cancer vaccines because preexistent T cell and antibody responses to HER-2 have been described in breast cancer patients (Disis and Cheever, 1996). In other words, breast cancer patients have preexisting immunity to the HER-2 receptor in the form of elevated antibody titers and T cell immunity. Elevated anti-HER-2 T cell responses have been demonstrated in breast and ovarian cancer patients following immunization with peptides derived from the HER-2 protein (Disis et al., 1999). However, whether peptide-specific T cell responses can be translated to antitumor immunity has yet to be established. 

Chen, C.H., Ji, H., Suh, K.W., Choti, M.A., Pardoll, D.M. and Wu, T.C. (1999) Gene gun-mediated DNA vaccination induces antitumor immunity against human papillomavirus type 16 E7-expressing murine tumor metastases in the liver and lungs. Gene Ther., 6, 1972-1981. 

Ciemik, F., Berzofsky, J.A. and Carbone, D.P. (1996) Induction of cytotoxic T lymphocytes and antitumor immunity with DNA vaccines expressing single T cell epitopes. J. Immunol., 156, 2369-2375. 

Tan, J., Yang, N.S., Turner, J.G., Niu, G.L., Maassab, H.F., Sun, J. etal. (1999) Interleukin-12 cDNA skin transfection potentiates human papillomavirus E6 DNA vaccine-induced antitumor immune response. Cancer Gene Then, 6, 331-339. 

T. Kinoshita Enzymes required for biosynthesis of GPI-anchored proteins H. Kunz Synthetic glycopeptides for the development of antitumor vaccines M. A. J. Ferguson GPI and glycoprotein biosynthesis as targets for anti-parasite design... 

Oniki S, Nagai H, Horikawa T, Furukawa J, Belladonna ML, Yoshhnoto T, Flara I, Nishigori C. Interleukin-23 and interleukin-27 exert quite different antitumor and vaccine effects on poorly immunogenic melanoma. Cancer Res 2006 66 6395—404. 

Beside the ABO blood group system a number of additional carbohydrate-based antigenic determinants are known (O Table 2), which are, however, not only recognized by antibodies. Some of them are more highly expressed on tumor cells and therefore can be described as tumor-associated antigens [115]. Synthetic tumor-associated antigens such as Lewis y or Globo H have been used in the development of antitumor vaccines [116,117]. 

Recently it was demonstrated that transfection of tumor cells with an antitumor peptide induced a protective immune reponse. Inoculation of mice with murine BD-2-transfected leukemia cells enhanced cytotoxic T lymphoc)des (CTL) and natural killer (NK) anti-tumor activity, with augmented IL-12 and IFN-y production. Animals vaccinated with transfected cells were protected against a challenge with parental cells (50% protection) and the vaccination generated leukemia-specific memory CTL [210]. 

Clinical studies using molecularly defined MHC class I-restricted antigens and peptides are being conducted in several institutions, and antigen-specific T-cell responses are detected after vaccination. However, the overall immune responses elicited by vaccination with CD8 T-cell peptides are weak and transient. Recently, several studies are demonstrating that to enhance antitumor immunity and eradicate tumor cells in patients, it is necessary to induce both CD4 and CD8" T-cell responses [285,291]. 

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