title: Immunogenicity of a plasmid DNA vaccine encoding chimeric idiotype in patients with B-cell lymphoma.
abstract: B-cell lymphomas express tumor-specific immunoglobulin, the variable regions of which [idiotype (Id)] can serve as a target for active immunotherapy. Promising results have been obtained in clinical studies of Id vaccination using Id proteins.However, Id protein is laborious and time-consuming to produce. DNA vaccination is an attractive alternative for delivering Id vaccines, because Id DNA can be rapidly isolated by PCR techniques. DNA coding for lymphoma Id can provide protective immunity in murine models. In the present study, we performed a Phase I/II clinical trial to study the safety and immunogenicity of naked DNA Id vaccines in 12 patients with follicular B-cell lymphoma. The DNA encoded a chimeric immunoglobulin molecule containing variable heavy and light chain immunoglobulin sequences derived from each patient's tumor, linked to the IgG2a and kappa mouse immunoglobulin (MsIg) heavy- and light-chain constant regions chains, respectively. Patients in remission after chemotherapy received three monthly i.m. injections of the DNA in three dose escalation cohorts of four patients each (200, 600, and 1800 micro g). After vaccination, 7 of 12 patients mounted either humoral (n = 4) or T-cell-proliferative (n = 4) responses to the MsIg component of the vaccine. In one patient, a T-cell response specific to autologous Id was also measured. Anti-Id antibodies were not detectable in any patient. A second series of vaccinations was then administered using a needle-free injection device (Biojector) to deliver 1800 micro g both i.m. and intradermally (i.d.); 9 of 12 patients had humoral (n = 6) and/or T-cell (n = 4) responses to MsIg. Six of 12 patients exhibited humoral and/or T-cell anti-Id responses; yet, these were cross-reactive with Id proteins from other patient's tumors. Subsequently, a third series of vaccinations was carried out using 500 micro g of human granulocyte-macrophage colony-stimulating factor DNA mixed with 1800 micro g of Id DNA. The proportion of patients responding to MsIg remained essentially unchanged (8 of 12), although humoral or T-cell responses were boosted in some cases. Throughout the study, no significant side effects or toxicities were observed. Despite the modest level of antitumor immune responses in this study, DNA vaccine technology retains potential advantages in developing anti-Id immunotherapies. Additional studies are warranted to optimize vaccine dose, routes of administration, vector designs, and prime-boost strategies. These results will help guide the design of such future DNA vaccine trials.
authors.affiliation: Division of Oncology, Department of Medicine, Stanford University School of Medicine, California 94305, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Timmerman
authors.forename: Gita
authors.initials: G
authors.lastname: Singh
authors.forename: Gary
authors.initials: G
authors.lastname: Hermanson
authors.forename: Peter
authors.initials: P
authors.lastname: Hobart
authors.forename: Debra K
authors.initials: DK
authors.lastname: Czerwinski
authors.forename: Behnaz
authors.initials: B
authors.lastname: Taidi
authors.forename: Ranjani
authors.initials: R
authors.lastname: Rajapaksa
authors.forename: Clemens B
authors.initials: CB
authors.lastname: Caspar
authors.forename: Adrienne
authors.initials: A
authors.lastname: Van Beckhoven
authors.forename: Ronald
authors.initials: R
authors.lastname: Levy
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D004306:Dose-Response Relationship, Immunologic; D005500:Follow-Up Studies; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D006801:Humans; D007130:Immunoglobulin Idiotypes / Q000235:genetics / Q000276:immunology*; D016233:Immunotherapy, Active / Q000379:methods*; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy; D010957:Plasmids / Q000235:genetics; D011241:Prednisone / Q000008:administration & dosage; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D019496:Cancer Vaccines; D007130:Immunoglobulin Idiotypes; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; D014750:Vincristine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide; D011241:Prednisone