Advantages of Vaccines That Induce Antibodies Over Vaccines Designed to Augment TLymphocyte Immunity

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The concept of a vaccine that consistently augments T-lymphocyte immunity against cancer cells is exciting and offers enormous potential for clinical benefit. However, demonstration that this has been achieved has proven to be more difficult than initially appreciated, for a variety of reasons:

1. Ideally, autologous cancer cells are required for testing and these are rarely available as cell lines or in frozen samples in sufficient quantities for a thorough analysis of the immune response and its specificity.

2. In vitro sensitization has in the past generally been required for demonstration of T-cell responses against tumor antigens and this adds significant risk of artifactual results and complicates the quantification of immune responses.

3. Augmentation of T-cell responses by vaccination in humans is more difficult to induce than augmentation of B-cell responses and has yet to be clearly achieved and confirmed in a majority of vaccinated patients against any tumor antigen.

4. Vaccine design depends on the immune response desired. There are hundreds of available approaches or combinations of approaches to inducing T-cell immunity. These include immunization with peptides or proteins with various adjuvants, dendritic cells pulsed with or transduced to express particular antigens, viruses or bacteria transduced to express antigens, and DNA or RNA vaccines. In each case these vaccines could include approaches to augmenting cytokine or second-signal induction. The range of options for augmenting T-cell immunity against cancer is daunting. Unlike the picture with vaccines designed to induce an antibody response where there is one best approach (conjugate vaccines as described below), it remains unclear which is the optimal approach for induction of T-cell immunity.

5. It is unclear whether augmentation of cytotoxic T lymphocytes (CTLs) or helper T cells is the desired goal for vaccines inducing T-cell immunity against cancer.

6. It is not clear which antigens should be selected as targets for T-cell attack against cancer, as no T-cell immune responses have been correlated with a more favorable prognosis as is true for antibody responses against glycolipids (GM2) and mucins (sTn) (10-12,51).

7. Tumor cells can and frequently do fail to express relevant antigens in the context of major histocompatibility complex (MHC) as a consequence of MHC loss or problems in antigen processing (proteosomes, TAP), or they may suppress the T-cell response or become resistant to it (by production of IL-10, TGF-P, VEGF, Fas-ligand, HLA-G, or Bcl-2) (reviewed in refs. 52 and 53).

Given these uncertainties, selection of a single vaccine approach for inducing optimal T-cell immunity, unlike the situation with antibody-inducing vaccines, is difficult now and will remain so for some years to come. Consequently, we have focused on antibody-inducing polyvalent vaccines targeting primarily the carbohydrate antigens listed in Table 1 plus a few glycoprotein antigens such as MUC1 and KSA (also termed EpCam) (54-58) in epithelial cancers, PSMA in prostate cancers, and CA125 (now termed MUC16) in ovarian cancers (59).

2. selection of cell-surface carbohydrate antigens as targets for immune attack against cancer

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