BISPECIFIC ANTIBODY-MEDIATED IMMUNOTHERAPY OF THE BCL(1) LYMPHOMA - INCREASED EFFICACY WITH MULTIPLE INJECTIONS AND CD28-INDUCED COSTIMULATION

The BCL(1) lymphoma in Balb/c mice can be successfully treated with bi specific (anti-CD3 x anti-idiotype) antibodies (BSABs). In these exper iments, animals were injected intraperitoneally (IP) with 5 x 10(3) tu mor cells (day 0) and treated with one single intravenous (IV) injecti on of 5 mu g BSAB (day 9). Because cross-linking of the CD3 complex is not in itself sufficient to activate resting T cells, the therapeutic success was mainly based on the progressive retargeting of the relati vely small cytotoxic T-lymphocyte effector cell pool already in existe nce in vivo. For this reason, the therapy lost its effectiveness at hi gher tumor loads, Two possibilities were explored to treat mice with a higher tumor load (10(5) tumor cells). First, multiple injections of BSABs were used, but a dose-related monovalent anti-CD3 immunosuppress ion was induced. This approach was only beneficial when the immune sys tem was able to recover from the previous injection of BSAB, As a seco nd approach, CD28 costimulation together with BSABs were used in an at tempt to activate resting T cells, ultimately enlarging the effector T -cell pool. However, we were repeatedly unsuccessful in attempts to im prove our in vivo results using young, naive animals in which the majo rity of T cells are of the naive phenotype. Only when animals were pri med to induce the memory T-cell type was a significantly better outcom e observed, and then only with multiple injections of BSABs and anti-C D28 monoclonal antibodies (MoAbs), rather than with BSAB or anti-CD28 MoAb alone, These results suggest that this combination was able to ac tivate memory and effector T cells and to focus them on the tumor, but was unable to activate naive T cells fully. The in vivo potency of th e BSAB and CD28 costimulation was shown by the fact that one-tenth of the quantity of BSAB was required to cure animals with 20 times the tu mor load. (C) 1996 by The American Society of Hematology.