Locoregional treatment of low-grade B-cell lymphoma with CD3�CD19 bispecific antibodies and CD28 costimulation: II. Assessment of cellular immune responses

Abstract

Ten patients with advanced B‐cell lymphoma were treated with a single locoregional injection of CD3×CD19 bispecific and costimulating CD28 monospecific antibodies to activate tumor‐infiltrating T‐lymphocytes. Antibodies were administered at 4 different dose levels (30 μg, 270 μg, 810 μg, 1,600 μg 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‐γ 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 CD3×CD19 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. © 2001 Wiley‐Liss, Inc.

Bi20 (fBTA05), a novel trifunctional bispecific antibody (anti‐CD20 × anti‐CD3), mediates efficient killing of B‐cell lymphoma cells even with very low CD20 expression levels

“…Interestingly, B-cell depletion was observed even at very low CD20 expression levels (patients CLL 11,12,13), confirming the results obtained in the allogeneic setting (Fig. 7).…”

“…However, despite promising in vitro efficacy, these molecules showed limited clinical benefit. [11][12][13] We previously reported the development of a new class of intact bispecific antibodies, trifunctional antibodies (trAbs), that features a special combination of mouse IgG2a and rat IgG2b isotypes, allowing the simultaneous redirection and activation of FcgRI/…”

A CD19-specific single-chain immunotoxin mediates potent apoptosis of B-lineage leukemic cells

“…11 However, interactions of therapeutic antibodies with Fc-receptors on a variety of effector cells can also cause detrimental effects. Bispecific antibodies targeting CD19 and CD3 showed potent effects against tumor cells in cell-culture assays but did not convince in clinical trials, 12,13 probably in part because they were absorbed by Fc-receptors on other cells than the intended effector cells. 14 To reduce these undesired effects, recombinant bispecific antibody constructs have been produced, consisting of single-chain Fv antibody fragments (scFvs) specific for CD19 fused to scFvs directed against trigger molecules on effector cells.…”

Role of 4-1BB:4-1BB ligand in cancer immunotherapy

“…63 A number of studies have demonstrated effective antitumor targeting in clinical trials using the costimulatory molecules but to date these have solely utilized the B7:CD28 pathway (Table 1). [64][65][66][67][68] Autoimmune disease may be initiated when T cells are inadvertently activated to respond to normal tissues perhaps due to concurrent viral infection. Evidence of the ways in which viruses can mis-direct the immune system and lead to autoimmune disease in humans are discussed in detail elsewhere.…”