Idiotype (Id) structures present on secreted monoclonal immunoglobulin (Ig) and on the surface Ig of clonal B cells in B-cell malignancies are tumor-specific antigens; as such, they are potential targets for specific anti-Id immunity (10,11). An intervention aimed at expanding Id-specific T cells with cytotoxic or suppressive effects on the tumor B-cell clone may be a feasible immunotherapeutic approach. Active immunization against idiotypic determinants on malignant B cells has produced resistance to tumor growth in transplantable murine B-cell lymphoma and plasmacytoma (12-15).
Kwak, Levy, and coworkers at Stanford University pioneered the vaccination of patients with B-cell lymphoma with Id protein derived from the patients' tumors (16,17). In their first report of nine treated patients with low-grade follicular lymphoma primarily at first remission after chemotherapy, each patient received a series of subcutaneous injections of autologous Id protein that had been conjugated to an immunogenic carrier protein, keyhole limpet hemocyanin (KLH). Id-specific humoral and/or cellular immune responses developed in seven of nine immunized patients. Tumor regression was observed in two patients who had measurable disease (16). In these patients, it was subsequently shown that cell-mediated cytolytic immune responses might be an important determinant of vaccine efficacy (18). In their follow-up study, 41 patients received a series of injections with vaccines consisting of Id protein coupled to KLH and emulsified in an immunological adjuvant, either incomplete adjuvant (5% squalane, 2.5% Pluronic L121, 0.2% Tween-80, and phosphate-buffered saline) or complete adjuvant (incomplete adjuvant containing increasing doses of threonyl-muramyl dipeptide). Among the first 32 patients in that trial vaccinated while in first remission, about one-half (14/32) mounted anti-Id immune responses to the vaccine. Long-term follow-up of these 32 patients, compared with nonresponders, revealed that the development of an immune response was strongly correlated with prolonged freedom from disease progression; overall survival was also superior in responding patients (17). These studies clearly demonstrate that Id protein can be formulated into an immunogenic, tumor-specific antigen in humans with lymphoma.
Since publication of the above studies, many groups have reported their results on Id-KLH vaccination in B-cell lymphoma. Among them, a study from Kwak's group at the National Cancer Institute showed a striking clinical benefit of the vaccine for patients (19). The investigators vaccinated 20 patients with follicular lymphoma in first complete remission following chemotherapy with Id-KLH and granulocyte-macrophage colony-stimulating factor (GM-CSF) administered locally as adjuvant. After vaccination, tumor-specific cytotoxic CD8+ and CD4+ T cells were found in 19 of 20 patients. Although anti-Id antibodies were detected, they appeared not to be required for antitumor clinical response. Presence of bcl-2 proto-oncogene product of the t(14;18) translocation characteristic of follicular lymphoma was monitored in the blood of these patients, and clearance of bcl-2 polymerase chain reaction (PCR) signal was achieved in 8 of 11 evaluable patients. In line with these results, a recent study from a Spanish group also showed clinical activity of Id-KLH vaccine in patients (20). Collectively, these studies demonstrate that Id-KLH vaccination is associated with clearance of residual tumor cells from blood and long-term disease-free survival in low-grade follicular lymphoma. Prospective, randomized trials have now begun to seek evidence of clinical benefit after Id vaccination in B-cell lymphoma. In addition, studies are under way to evaluate the efficacy of Id-KLH vaccines to treat patients who have relapsed indolent non-Hodgkin's lymphoma (21) or have undergone myeloablative therapy (22), and patients with mantle cell lymphoma (23-25).
To apply Id-based vaccination to large numbers of patients, it is crucial to develop feasible and rapid methods, other than the currently used hybridoma technique, to prepare Id protein or its fragment from each patient. Several alternative sources of recombinant Id proteins are now available for clinical study. These include Id proteins produced in a variety of genetically engineered organisms. The first among these that are currently being evaluated under phase I/II clinical trials are Id proteins produced in transfected mammalian cells grown in tissue culture (26) and plant-derived single-chain variable region (scFv) Id fragments (27). It has been shown that Id proteins from lymphoma patients' specimens can be produced in recombinant bacteria and that DCs pulsed with these proteins (secreted as Fab fragments) can stimulate Id-specific cytotoxic T lymphocytes (CTLs) in vitro (28). Furthermore, the tobacco mosaic virus has been exploited as a vector for engineering protein production in tobacco plants. In a preclinical study, vaccination of mice with plant-derived Id scFv was able to elicit tumor protection equivalent to that of Id-KLH plus adjuvant (29). On the basis of these results, a phase I/II clinical study has been initiated to evaluate the efficacy of plant-derived Id scFv vaccine in patients with follicular lymphoma (27).
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