Induction of Immune Responses in Patients with B-Cell Lymphoma against the Surface-Immunoglobulin Idiotype Expressed by Their Tumors

The idiotypic determinants of the surface immunoglobulin of a B-cell lymphoma can serve as a clonal tumor-specific marker, which may have implications for immunotherapy. We sought to determine whether idiotype-specific immune responses against this autologous antigen could be induced in patients with B-cell lymphoma. Nine patients were selected who had minimal residual disease or a complete remission after chemotherapy. Each received a series of subcutaneous injections of the immunoglobulin derived from his or her tumor cells (immunoglobulin-idiotype protein), which had been conjugated to a protein carrier and mixed with an immunologic adjuvant. In seven of the nine patients the injections induced sustained idiotype-specific immunologic responses of the humoral type (two patients), the cell-mediated type (four patients), or both (one patient). The use of an adjuvant was essential for these immune responses. The induced antibodies bound specifically to autologous immunoglobulin idiotype, inhibited the binding of murine monoclonal antiidiotype antibodies, and bound autologous tumor cells. Cell-mediated responses were demonstrated by the specific proliferation of immune peripheral-blood mononuclear cells to the soluble immunoglobulin-idiotype protein in vitro. The tumors of both of the patients with measurable disease regressed completely. Toxicity associated with the vaccine was minimal and consisted only of mild reactions at the site of intramuscular injection. These results demonstrate that autologous immunoglobulin idiotype can be formulated into an immunogenic, tumor-specific antigen in humans with B-cell lymphoma, and they provide the background for large-scale trials of active specific immunotherapy of this disease. (N Engl J Med 1992;327:1209–15.), IMMUNOGLOBULIN molecules are composed of heavy and light chains, which possess highly specific variable regions at their amino termini. The variable regions of heavy and light chains combine to form the unique antigen-recognition site of the immunoglobulin protein. These variable regions contain determinants (molecular shapes) that can themselves be recognized as antigens or idiotypes. B-cell tumors are composed of clonal proliferations of cells synthesizing a single antibody molecule with unique variable regions in the heavy and light chains. B-cell lymphomas are neoplasms of mature resting and reactive lymphocytes, which generally express synthesized immunoglobulin on the cell surface. The idiotypic determinants…