B-cell lymphoma idiotypes chimerized by gene targeting can induce tumor immunity

Abstract

Immunization with modified immunoglobulin (Ig) idiotypes (Ids) of B-cell lymphomas is an attractive approach of experimental tumor immunotherapy. We show here that B-lymphoma cells can be gene-modified by homologous recombination at the Ig heavy chain locus. Although it has been demonstrated previously that a protein vaccine containing a mouse/human chimeric Ig had no immunostimulatory effect, we show that a xenogeneic Fc segment attached to the Id by gene targeting in autologous murine tumor cells can serve as an immunogenic carrier and is capable of inducing tumor protection. A prerequisite for successful vaccination is the delivery of tumor cells that have been engineered to express the Id in the chimeric form rather than administration of the soluble chimeric protein. Also DNA vaccination with plasmids encoding chimeric Ids was reported to induce an anti-idiotypic response, suggesting that there might be related mechanisms such as enhanced antigen presentation. Immunization with engineered lymphoma cells is a very potent protocol: in the cell-based setting, minute levels of expression in the gene-targeted cells are sufficient to confer tumor immunity. Because the titers of anti-Id antibodies induced do not reflect the degree of tumor protection, the immune mechanisms responsible for tumor rejection cannot be ascribed exclusively to a humoral response. Cancer Gene Therapy (2000) 7, 501-506

Immunization with a Recombinant Adenovirus Encoding a Lymphoma Idiotype: Induction of Tumor-Protective Immunity and Identification of an Idiotype-Specific T Cell Epitope

“…One possibility is that some tumor idiotypes do not contain CTL-binding motifs. However, idiotype-specific CTLs have been clearly demonstrated against human idiotypes (10 -12), and in some murine models the tumor protection cannot be fully attributed to an anti-idiotypic Ab response (15,17,18), suggesting that T cell-mediated immunity may play a role in tumor eradication. It is possible that the in vitro systems used to expand and identify idiotype-specific T cells in such studies may need to be optimized to demonstrate such an immune response.…”

Targeted DNA vaccines for enhanced induction of idiotype-specific B and T cells

“…Finally, B lymphoma cells were generated that by gene targeting had their endogenous heavy (H) chain replaced by a human H chain. Such engineered lymphoma cells were used to immunize mice, and induced a T cell-mediated protection against wild-type B cell lymphoma (Selmayr et al, 2000). These studies have contributed interesting approaches for Id-immunization, but will not be discussed further as they are not examples of APC-targeted DNA Id-vaccines, which is the theme of the present paper.…”

Potential of the Trifunctional Bispecific Antibody Surek Depends on Dendritic Cells: Rationale for a New Approach of Tumor Immunotherapy

“…Numerous antitumor vaccination protocols have been elaborated on the basis of transfer of DCs that were generated in vitro and pulsed with tumor-derived proteins or peptides or transduced with TAA-encoding gene constructs (2)(3)(4). However, immunization against a single antigen can result in selection of antigen loss mutants and is therefore inferior to polyvalent, whole cell-based immunization strategies where even yet-unidentified antigens can be included (5)(6)(7)(8)(9).…”