Phase I Trial of a Novel Intradermal Idiotype Vaccine in Patients with Advanced B-Cell Lymphoma: Specific Immune Responses Despite Profound Immunosuppression

Abstract

The immunoglobulin receptor of B-cell lymphomas constitutes a specific tumor antigen (idiotype) and a target for active immunotherapy. Encouraging results have been reported in phase II trials after s.c. vaccination of follicular lymphoma patients during clinical remission with idiotype produced from eukaryotic cell lines and coupled to an immunogenic carrier macromolecule. We have developed a good manufacturing protocol for rapid expression of idiotype vaccines as recombinant Fab fragments in Escherichia coli. The objectives of this trial were to show safety and feasibility of intradermal immunization with this vaccine and to investigate whether immune responses were induced by this immunization route. Patients (n = 18) with advanced B-cell malignancies received repetitive intradermal vaccinations with 0.5 to 1.65 mg recombinant idiotype Fab fragment mixed with lipid-based adjuvant in combination with 150 Mg granulocyte macrophage colony-stimulating factor s.c. at the same location. The patients' immune status was assessed by flow cytometry of peripheral blood lymphocytes and concomitant hepatitis B vaccination. Cellular and humoral immune responses to the vaccine were assessed by enzyme-linked immunospot and ELISA. Side effects of a total of 65 vaccinations were mild and did not affect the immunization schedule. No patient developed hepatitis B surface antibodies (anti-HBs) after two hepatitis B immunizations. Of 17 evaluable patients, five developed specific anti-vaccine antibodies, and eight developed anti-Fab T-cell responses. T-cell reactivity was independent of the cellular immune status and was idiotype specific as shown by statistical regression analysis (P = 0.0024) and epitope mapping studies. Intradermal administration of uncoupled recombinant idiotype with appropriate adjuvants may overcome profound clinical immunosuppression and induce specific immune responses. (Cancer Res 2006; 66(8): 4496-502)

Comparative analysis of predicted HLA binding of immunoglobulin idiotype sequences indicates T cell–mediated immunosurveillance in follicular lymphoma

“…9 Peptide mapping experiments revealed that these T-cell responses are consistently directed against human leukocyte antigen (HLA) class I-restricted peptides from the complementarity-determining regions (CDRs) or against hypermutated idiotype epitopes. 8,9 These findings are in accordance with animal studies demonstrating T-cell tolerance for germlineencoded immunoglobulin sequences but responsiveness to novel idiotopes arising from junctional diversity or somatic mutations. 10 Because mouse models have also shown T cell-mediated immunosurveillance against hypervariable idiotypic peptides, 11 we sought to obtain evidence that spontaneous idiotype-directed T-cell immunity is operational in nonimmunized lymphoma patients and impairs expansion of malignant B-cell clones that express an idiotype with high immunogenicity.…”

“…Most of these bona fide peptides are expected to physically bind to HLA and to serve as functional T-cell epitopes. 8,9,[16][17][18] In a matched-pair comparison of the idiotype BIMAS sum scores, the V H region of an affected patient's own lymphoma had lower HLA-binding scores than allogeneic idiotypes (Figure 1). No such global difference was observed for idiotype V L regions.…”

“…7 Immunization with recombinant idiotype F ab fragments induces idiotype-directed T cells in the majority of patients. 8,9 In the first trial testing idiotype vaccination as upfront intervention without prior cytoreductive therapy, anti-idiotype T-cell responses correlated with superior progression-free survival and with durable lymphoma remissions. 9 Peptide mapping experiments revealed that these T-cell responses are consistently directed against human leukocyte antigen (HLA) class I-restricted peptides from the complementarity-determining regions (CDRs) or against hypermutated idiotype epitopes.…”

Evidence for idiotype-directed immunosurveillance is restricted to follicular lymphoma and attributable to somatic hypermutation

“…Lymphoma samples were obtained with written informed consent from the Freiburg University idiotype vaccination program [2][3][4] and the hematology biobank of Leiden University Medical Center with approval of the ethics committee of Freiburg University. HLA alleles were identified by serotyping and high-resolution genotyping (Olerup SSP kit, Qiagen, Hilden, Germany).…”

TCL1: a shared tumor-associated antigen for immunotherapy against B-cell lymphomas

“…[5][6][7][8][9][10][11] Idiotype vaccines were shown to be safe and induced sustained antitumor antibody and CD4 ϩ and CD8 ϩ T-cell responses in patients with follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). [5][6][7][8][9][10][11] Furthermore, idiotype vaccines induced molecular remissions when administered after standard chemotherapy. 10 A recently completed randomized, double blind, multicenter phase 3 clinical trial showed that idiotype vaccination improves disease-free survival when administered in the setting of minimal residual disease in FL, providing proof of principle that therapeutic vaccines can improve clinical outcome in these patients.…”