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Bispecific antibody-mediated immunotherapy of the BCL1 lymphoma: increased
efficacy with multiple injections and CD28-induced costimulation
C Demanet, J Brissinck, J De Jonge and K Thielemans
Physiology Department of the Medical Faculty of Brussels Free University,
Belgium.
The BCL1 lymphoma in Balb/c mice can be successfully treated with
bispecific (anti-CD3 x anti-idiotype) antibodies (BSABs). In these
experiments, animals were injected intraperitoneally (IP) with 5 x 10(3)
tumor cells (day 0) and treated with one single intravenous (IV) injection
of 5 micrograms 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 relatively
small cytotoxic T-lymphocyte effector cell pool already in existence in
vivo. For this reason, the therapy lost its effectiveness at higher 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 immunosuppression was induced. This
approach was only beneficial when the immune system was able to recover
from the previous injection of BSAB. As a second approach, CD28
costimulation together with BSABs were used in an attempt to activate
resting T cells, ultimately enlarging the effector T-cell pool. However, we
were repeatedly unsuccessful in attempts to improve our in vivo results
using young, naive animals in which the majority of T cells are of the
naive phenotype. Only when animals were primed to induce the memory T-cell
type was a significantly better outcome observed, and then only with
multiple injections of BSABs and anti-CD28 monoclonal antibodies (MoAbs),
rather than with BSAB or anti-CD28 MoAb alone. These results suggest that
this combination was able to activate 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 the 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 tumor load.
Volume 87,
Issue 10,
pp. 4390-4398,
05/15/1996
Copyright © 1996 by The American Society of Hematology
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