Patients with various epithelial cancers have been immunized with unclustered TF-KLH and sTn-KLH vaccines plus various adjuvants (84,85). High-titer IgM and IgG antibodies against TF and sTn antigens resulted. In our hands the majority of the reactivity was against antigenic epitopes present in the vaccine that were not present on naturally expressed mucins (porcine or ovine submaxillary mucins [PSM or OSM]) or tumor cells (84,86). Based on previous studies with Tn antigen (87), Kurosaka and Nakada et al. hypothesized that MLS102, a monoclonal antibody against sTn, might preferentially recognize clusters ((c)) of sTn (88). Studies with monoclonal antibody B72.3 and with sera raised against TF-KLH and sTn-KLH conjugate vaccines in mice and in patients resulted in the same conclusion (41,84,86). The availability of synthetic TF, Tn, and sTn clusters consisting of three epitopes covalently linked to three consecutive serines or threonines has permitted proof of this hypothesis. In both direct tests and inhibition assays, B72.3 recognized sTn clusters exclusively, and sera from mice immunized with sTn (c)-KLH reacted strongly with both natural mucins and tumor cells expressing sTn (41). Based on this background, we initiated trials with the TF(c)-KLH, Tn(c)-KLH, and sTn(c)-KLH conjugate vaccines in patients with breast cancer. Antibodies of relevant high titer and specificity, including against OSM or PSM and cancer cells expressing TF, Tn, or sTn, were induced for the first time in our experience (Table 3). Based on these results, we plan to include clustered Tn, sTn, and TF in the polyvalent vaccines against epithelial cancers.
Several trials with TF, Tn, and sTn vaccines have been reported from other centers, and a large multicenter phase III trial with an sTn vaccine has been completed. George Springer's pioneering trials in breast cancer patients with vaccines containing TF and Tn purified from natural sources and mixed with typhoid vaccine (as adjuvant) began in the mid-1970s (34,89,90). DTH and IgM responses against the immunizing antigens and prolonged survival compared to historical controls were reported. MacLean immunized 10 ovarian cancer patients with synthetic TF conjugated to KLH plus immunological adjuvant Detox (monophosphoryl Lipid A plus BCG cell-wall skeletons) and described augmentation of IgG and IgM antibodies against synthetic TF in 9 of 10 patients (85). Lower levels of antibody reactivity against TF from natural sources were detected in some of these cases. MacLean has also immunized patients with breast and other adenocarcinomas with sTn-KLH plus Detox (13,51,91). Induction of IgM and IgG antibodies against synthetic and natural sources of sTn was seen in essentially all patients and this response was further increased by pretreatment of patients with a low dose of cyclophosphamide. Reactivity of these sera with natural mucins and tumor cells despite the use of an unclustered sTn vaccine is probably explained by the fourfold higher sTn/KLH epitope ratio achieved in the MacLean vaccine compared to our previous unclustered vaccine. Survival appeared to be improved overall compared to historical controls and patients who responded with high antibody titers survived longer than those with lower titers. Reactivity with breast cancer cells, including CDC, was described. This is the basis for the completed multicenter phase III randomized trial of the sTn-KLH plus Detox vaccine vs KLH alone plus Detox in breast cancer patients with stable disease or clinical response to chemotherapy. Although the sponsor's website reports this study did not reach its primary endpoint, subgroup analysis is being performed.
Initial attempts at preparing a vaccine against polysialic acid for use in military recruits who are at risk of group B meningococcus infection were unsuccessful. We also have completed analysis of a clinical trial with polysialic acid conjugated to KLH plus QS-21 and found that no antibody response could be induced. Consequently, we tested a second polysialic acid vaccine that had been modified (N-propionylated) to increase its immu-nogenicity in collaboration with Dr. Harold Jennings, who pioneered the use of N-propionylation for this purpose (92). This induced an antibody response against unmodified polysialic acid in five of six patients immunized (see Fig. 3). These vaccine-induced antibodies also reacted with SCLC cells (and were cytotoxic for antigen-positive bacteria). This N-propionylated polysialic acid vaccine is suitable for inclusion in our polyvalent vaccine against SCLC and possibly for trials in students and military recruits for prevention of group B meningococcus infections.
4. effector mechanisms of antibodies against cell-surface antigens
Immunization against the carbohydrate components generally results exclusively in an antibody response (see 15-17 for dissenting views), primarily an IgM antibody response. These IgM antibodies are known to induce complement activation resulting in inflammation, and phagocytosis of tumor cells by the reticuloendothelial system (opsonization) and CDC (reviewed in 1). IgG antibody responses can also induce complement activation (regarding IgG depending on the subclass, IgG1 and IgG3 being optimal in humans), and these same effector mechanisms. IgG antibodies of these subclasses are also known to induce ADCC. Serological analysis of the series of clinical trials described above has suggested that the six vaccines containing different glycolipids induced antibodies mediating CDC whereas the four vaccines containing carbohydrate or peptide epitopes carried by mucin molecules induced antibodies that were not capable of mediating CDC. To determine whether this dichotomy was a result of the properties of the induced antibodies (i.e., class and effector functions), the different target cells used, or the nature of the target antigens, we compared the cell-surface reactivity (assayed by FACS), complement-fixing ability (using the immune adherence [IA] assay), and the CDC activity of a panel of monoclonal antibodies and immune sera from these trials on the same two tumor cell lines. Antibodies against glycolipids GM2, globo H and Ley, protein KSA, and mucin antigens Tn, sTn, TF, and MUC1 all reacted with these antigens expressed on tumor cells and all fixed complement. CDC, however, was mediated by antibodies against the glycolipids and a globular protein (KSA), but not by antibodies against the mucin antigens.
It must be emphasized that although we showed that mucins are poor targets for complement-mediated lysis of tumor cells, studies have shown that induction of antibodies against either glycolipid or mucin antigens results in protection from tumor recurrence in several different preclinical mouse models (reviewed in refs. 8 and 9). Also, antibodies against either glycolipid or mucin epitopes correlate with a more favorable prognosis in patients (11-13,90). It does not appear that the inability of antibodies against mucin antigens to induce complement-mediated lysis is necessarily detrimental to the antitumor response. Consequently, complement-mediated inflammation, opsonization, and ADCC but not CDC are likely mechanisms for the prolonged survival seen in the preclinical experiments targeting mucin antigens and suggested in the clinical trials with passively administered and actively induced antibodies against mucin antigens. Regarding bacterial infections, this is supported by the severe consequences of hereditary deficiency states involving either the classical or alternate complement pathways and the comparatively trivial consequences to deficiencies of the complement membrane attack complex (93).
The majority of even cancer patients who will eventually die of their cancer can initially be rendered free of detectable disease by surgery and/or chemotherapy. Adjuvant chemotherapy or radiation therapy at this point are generally only minimally beneficial, so there is real need for additional methods of eliminating residual circulating cancer cells and micrometastases. This is the ideal setting for treatment with a cancer vaccine. The immune response induced is critically dependent on both vaccine design and awareness of the antigenic epitope. For antibody induction there is one best vaccine design, conjugation of the antigen to an immunogenic protein such as KLH and the use of a potent adjuvant such as the saponins QS-21 and GPI-0100. This approach alone induced strong antibody responses against the glycolipids GM2, fucosyl GM1 and globo H, and cancer cells expressing these glycolipids. Other carbohydrate antigens require additional modifications to augment relevant immunogenicity. GD2 and GD3 lactones and N-propionylated polysialic acid were significantly more effective at inducing antibodies against the unmodified antigens and tumor cells expressing these antigens. Tn, sTn, and TF trimers (clusters) were significantly more effective than the monomers at inducing antibodies reactive with the cancer-cell surface.
Antibodies are ideally suited for eradicating pathogens from the bloodstream and from early tissue invasion. Passively administered and vaccine-induced antibodies have accomplished this, eliminating circulating tumor cells and systemic or intraperitoneal micrometastases in a variety of preclinical models, so antibody-inducing vaccines offer real promise in the adjuvant setting. Polyvalent vaccines will probably be required because of tumor cell heterogeneity, heterogeneity of the human immune response, and the correlation between overall antibody titer against tumor cells and antibody effector mechanisms. Over the next several years, phase II clinical trials designed to determine the clinical impact of polyvalent conjugate vaccines will be initiated in the adjuvant setting in patients with SCLC and several epithelial cancers.
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