Locoregional treatment of low-grade B-cell lymphoma with CD3xCD19 bispecific antibodies and CD28 costimulation. II. Assessment of cellular immune responses.
Ten patients with advanced B-cell lymphoma were treated with a single locoregional injection of CD3xCD19 bispecific and costimulating CD28 monospecific antibodies to activate tumor-infiltrating T-lymphocytes. Antibodies were administered at 4 different dose levels (30 microg, 270 microg, 810 microg, 1,600 microg of each antibody) either by intratumoral or intralymphatic injection. Most patients developed responses within different compartments of the immune systems (T cells, NK cells) subsequent to the antibody application. Comparative studies in 2 patients of which treated as well as untreated lymph nodes were available revealed the up-regulation of T-cell activation markers induced by the antibody injection. Additionally, in 1 patient the induction of apoptosis of lymphoma B cells in the antibody-treated lymph node was observed. Specificity analyses of peripheral blood T cells by means of IFN-gamma ELISpot measurement indicated the recruitment of idiotype-specific T cells, as in 1 out of 3 investigated patients an increased T-cell response toward autologous idiotype peptides could be demonstrated. We conclude that a single injection of CD3xCD19 bispecific antibodies is capable to induce an activation of autologous T lymphocytes if simultaneous costimulatory signaling by CD28 antibodies is provided. Furthermore, our data suggest that at least in some patients lymphoma-specific T cells can be recruited by this immunotherapeutic approach toward B-cell lymphoma.
Manzke
O
O
University of Cologne, Department of Internal Medicine I, Joseph-Stelzmann-Str.9, D-50925 Cologne, Germany.
Tesch
H
H
Lorenzen
J
J
Diehl
V
V
Bohlen
H
H
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage / Q000627:therapeutic use*; D018941:Antigens, CD19 / Q000627:therapeutic use*; D017209:Apoptosis; D018106:CD28 Antigens / Q000627:therapeutic use*; D017252:CD3 Complex / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000096:biosynthesis; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D007167:Immunotherapy; D020287:In Situ Nick-End Labeling; D007694:Killer Cells, Natural / Q000378:metabolism; D015448:Leukemia, B-Cell / Q000628:therapy; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism; D008213:Lymphocyte Activation; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000628:therapy*; D008224:Lymphoma, Follicular / Q000628:therapy; D020522:Lymphoma, Mantle-Cell / Q000628:therapy; D008297:Male; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D015854:Up-Regulation
D018033:Antibodies, Bispecific; D018941:Antigens, CD19; D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D006684:HLA-DR Antigens; D007136:Immunoglobulins