Idiotype-encoding recombinant adenoviruses provide protective immunity against murine B-cell lymphomas.

Vaccination with tumor-specific immunoglobulin or idiotype (Id) is a promising new form of immunotherapy for B-cell malignancies. Id protein vaccination has demonstrated clinical activity in B-cell lymphomas, yet it requires the laborious and time-consuming procedures of tumor-myeloma cell hybridization, large-scale in vitro culture, and protein purification. Recombinant adenoviruses are highly efficient and immunogenic gene transfer vehicles from which individualized vaccines can be rapidly assembled using polymerase chain reaction-amplified tumor Id genes. Id-encoding adenoviruses were evaluated as vaccines in 2 murine B-cell lymphoma models. A single injection of recombinant Id adenovirus provided protection from subsequent tumor challenge that was equivalent or superior to that afforded by Id protein vaccination. Protected mice had substantial serum titers of Id-specific antibodies. When used in conjunction with chemotherapy, vaccination also prolonged the survival of mice bearing pre-existing tumor. Mechanistic studies demonstrated that tumor protection was not dependent upon T cells. Importantly, in mice prevaccinated with an irrelevant adenovirus, tumor protection following vaccination with Id adenovirus was not significantly impaired. These findings have implications for the design of future lymphoma immunotherapy trials.

Cytokine fusion constructs as DNA vaccines against tumors.

Various studies have used DNA vaccination as a method of immunizing against tumors (1-12). As with any tumor vaccine, one challenge is to find a truly tumor-specific antigen (13,14). The majority of immunologically targeted tumor antigens are also expressed on a subset of normal host cells. Examples of such antigens include prostate-specific antigen, and CD20, a B cell marker. Some tumor antigens are specific for activated cells of certain types, such as carcinoembryonic antigen (CEA) or the IL-2 receptor. These are often found on embryonic or fetal cells as well as tumor cells. The carbohydrate antigens of melanomas and the immunoglobulin (Ig) idiotype of B cell lymphomas represent tumor-specific antigens (TSA). Unfortunately, TSA have not been identified in more common malignancies. Furthermore, the antigenic determinants of known TSA may differ between patients; for example, the tumor idiotype (Id) of B cell lymphoma is highly patient-specific and must be determined for each case.

DNA vaccination against the idiotype of a murine B cell lymphoma: mechanism of tumor protection.

Several studies have shown that immunization with DNA, which encodes the idiotypic determinants of a B cell lymphoma, generates tumor-specific immunity. Although induction of antiidiotypic Abs has correlated with tumor protection, the effector mechanisms that contribute to tumor protection have not been clearly identified. This study evaluated the tumor protective effects of humoral and cellular immune mechanisms recruited by idiotype-directed DNA vaccines in the 38C13 murine B cell lymphoma model. Antiidiotypic Abs induced by DNA vaccination supported in vitro complement-mediated cytotoxicity of tumor cells, and simultaneous transfer of tumor cells and hyperimmune sera protected naive animals against tumor growth. However, in vitro stimulation of immune splenocytes with tumor cells failed to induce idiotype-specific cytotoxicity, and following vaccination, depletion of CD4 or CD8 T cell subsets did not compromise protection. Furthermore, protection of naive recipients against tumor challenge could not be demonstrated either by a Winn assay approach or by adoptive transfer of spleen and lymph node cells. Thus, in this experimental model, current evidence suggests that the tumor-protective effects of DNA vaccination can be largely attributed to idiotype-specific humoral immunity.

Tumor-specific idiotype vaccines in the treatment of patients with B-cell lymphoma--long-term results of a clinical trial.

The surface Ig on each B-cell lymphoma has unique portions (idiotypes), which can be recognized by the immune system. In this study, we immunized patients against the Ig expressed by their tumor and observed their clinical outcomes. After standard chemotherapy, 41 patients with non-Hodgkin's B-cell lymphoma received a series of injections with a vaccine consisting of tumor Ig protein coupled to keyhole limpet hemocyanin and emulsified in an immunologic adjuvant. Subjects were observed for toxicity, immune responses, and tumor status. The median duration of follow-up of all patients is 7.3 years from diagnosis and 5.3 years from the last chemotherapy given before vaccine treatment. Twenty patients (49%) generated specific immune responses against the idiotypes of their tumor Ig. Two patients who had residual disease experienced complete tumor regression in association with the development of these immune responses. The median duration of freedom from disease progression and overall survival of all 20 patients mounting an anti-idiotype immune response are significantly prolonged compared to the patients who did not mount an immune response. Thirty-two patients were in their first remission and nine were in subsequent remissions before beginning vaccine treatments. Analysis of the 32 first remission patients also shows an improved clinical outcome for those patients who mounted a specific immune response compared to those who did not (freedom from progression, 7.9 years v 1.3 years P = .0001; median survival from time of last chemotherapy not yet reached v 7 years, P = .04). This study confirms an earlier report that patients with B-cell lymphoma can be induced to make a specific immune response against the Ig expressed by their own tumor. It further shows that the ability to make such an immune response is correlated with a more favorable clinical outcome. Prospective controlled trials will be needed to prove a causal relationship between anti-idiotype immunity and improved clinical outcome.

DNA immunization induces protective immunity against B-cell lymphoma.

Idiotypic determinants of the immunoglobulin expressed on the surface of B-cell lymphomas are tumor-specific antigens (TSAs), which can be targeted by immunotherapy. Immunization with DNA constructs encoding the idiotype (ld) of a murine B-cell lymphoma induced specific anti-ld antibody responses and protected mice against tumor challenge. Use of DNA encoding an ld/GM-CSF (idiotype/granulocyte-macrophage colony-stimulating factor) fusion protein improved vaccine efficacy, and xenogeneic immunoglobulin constant region determinants were required for immunogenicity. These results indicate that DNA may be a simple and efficacious means of inducing immune responses against a weak, otherwise unrecognized tumor antigen, provided that additional stimuli are included with the DNA.