While we have seen both immune mechanisms for the successful destruction of neoplastic cells by the host as well as the ability of the neoplasms to escape such host immune mechanisms, the promise of utilizing this delicate immunological balance for the control and/or elimination of the neoplasm has not yet been realized. Our knowledge of immune mechanisms, both at the biolog- ical and molecular level, has increased exponentially during the last two or three decades. The use of immunotherapeutic measures, alone or in conjunction with other types of therapy, has only rarely led to a complete cure of the disease, while surgery, radiation, and chemotherapy have all been successful in eradication of neoplastic disease in hundreds of thousands of pa-tients. Despite this failure, the search for a successful immunotherapeutic regimen leading to the cure of neoplastic disease continues at an even greater pace.
The first clinical use of a vaccine in the treatment of cancer was reported by Coley (1893) more than a century ago. The vaccine consisted of extracts of pyogenic bacteria with the object of stimulating a generalized immune response that would hopefully include the neoplasm. Since that time, and mostly in recent years, a number of other attempts have been made to produce a variety of vaccines aimed at inducing both cellular and humoral immunity toward antigens within specific neoplasms and also those that induce a more generalized enhancement of the immune response. Earlier studies simply utilized extracts or fractions of neoplastic cells, which were injected directly into the patient with or without various adjuvants. Adjuvants consisted of various simple or complex molecules known to enhance the immune response in general such as killed bacteria, complex polysaccharides, and certain lipids. More recently, however, cancer vac- cines have become better defined and are used with specific targets or purposes, such as enhan- cing specific types of immunity. In Table 19.15 may be seen a listing of various types of acellular cancer vaccines and their targeted neoplasm or neoplastic condition.
Since neoplasms exhibit altered surface glycoproteins and gangliosides (Chapter 15), the potential for immunological responses to such structures is to be expected and has been demon- strated (cf. Livingston, 1992). Modification of autologous cancer cells and components with haptens, especially dinitrophenyl, produces altered proteins on the surface of such neoplastic cells, resulting, presumably, in immune reactions to both hapten-modified cells and unmodified cells. In this way, T-cell clones reactive to antigens on the surface of the neoplastic cell would be expected to occur (Berd et al., 1998). In certain neoplasms, especially lymphomas and myelo- mas producing excessive amounts of antibodies, use of the specific antibody produced by the neoplastic cells as an idiotype vaccine would be expected to produce antibodies and cell-medi- ated reactions to that specific antigen (Bianchi and Massaia, 1997). As was discussed earlier (Figure 19.20), some mucoproteins on neoplasms are underglycosylated and thus offer potential antigens for vaccination (Finn et al., 1995). Since specific peptide epitopes to antigens presented
Table 19.15 Cancer Vaccines—Noncellular
by the MHC proteins of neoplastic cells have now been identified, such as those related to MAGE, GAGE, CEA, and others (Celis et al., 1995), it is possible to utilize such peptides as vaccines in association with various adjuvant or enhancement techniques (Rosenberg, 1996). Regressions of metastatic melanoma in patients treated with an antigen peptide encoded by the MAGE-3 gene presented by HLA-A1 in patients have been described (Marchand et al., 1999). Vaccines developed to proto-oncogene products, especially the ras family (Fenton et al., 1995; Halpern, 1997), and telomerase (Minev et al., 2000), a protein virtually absent in most adult cell types, have been used experimentally. Similarly, heat-shock proteins, when isolated from neo- plastic cells, are usually complexed with a wide array of peptides. Such complexes have been utilized as vaccines in a variety of animal studies (Przepiorka and Srivastava, 1998). Vaccines against tumor-specific antigens have been employed predominantly against melanoma (Berd and Mastrangelo, 1993). By far the most successful preventive vaccines have been with virus- induced neoplasms, particularly hepatitis B in the human (Blumberg, 1997). Other known herp- esviruses including the EBV and HSV-8 viruses are also potential candidates for the develop- ment of preventive vaccines (cf. Fischinger, 1992). Clinical trials are already under way with preventive and therapeutic vaccines for human papillomavirus-associated cervical cancers (Ling et al., 2000).
Recently, whole cells modified either by transfection, virus infection, or hybridization have been utilized as vaccines against specific neoplasms or more general enhancement of the host immune response. Cellular immunity in chimpanzees to human tumor-associated mucins has been effected by vaccination with Epstein-Barr virus–immortalized autologous B cells trans- fected with the MUC-1 cDNA (Pecher and Finn, 1996). In another experimental system, New- ton et al. (2000) utilized a cell line for the formation of cell hybrids after fusion with patient- derived neoplastic cells. The hybrid cells were then irradiated to prevent their replication and inoculated as a vaccine into patients with melanoma or adenocarcinoma. Another method of cel- lular cancer vaccination is the transfection of neoplastic cells from the host with genes of spe- cific antigens, cytokines, or costimulatory molecules involved in the interaction of T cells and neoplastic cells. In experimental systems, a variety of genes for different cytokines and costimu- latory molecules have been transfected into specific neoplastic cells (cf. Forni et al., 1995). The rationale here is that the reinoculated cells will markedly stimulate the host-immune system to the neoplasm containing the transfected genes as well as the identical neoplasm in the host. A similar rationale has been used in transfecting specific antigens into neoplastic cells (e.g., Schweighoffer, 1996).