article accepted in Cancer Immunology, Immunotherapy
Evaluating combinations of costimulatory antibody-ligand fusion proteins for targeted cancer immunotherapy
Nora Hornig, Katharina Reinhardt, Vanessa Kermer, Roland E. Kontermann, Dafne
Müller
Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569
Stuttgart, Germany.
Abstract:
Combinatory strategies are becoming of increasing interest in cancer immunotherapy.
Costimulation by individual members of the immunoglobulin-like (Ig)- and TNF superfamily have
already shown promising antitumor potential, thus prompting the exploration of their synergistic
abilities in combinatorial approaches. Here, we pursued a targeted strategy with antibody-fusion
proteins composed of a tumor-directed antibody and the extracellular domain of the costimulatory
ligand B7.1, 4-1BBL, OX40L, GITRL or LIGHT, respectively. Costimulatory activity was assessed in an
experimental setting where initial T cell activation was induced by a bispecific antibody
(tumor-related antigen × CD3). Advantage of combined targeted costimulation was shown for either
B7.1 or 4-1BBL with OX40L, GITRL, LIGHT and 4-1BBL in terms of T cell proliferation and IFN-γ
release. Since encouraging results were obtained by the combination of B7.1 and 4-1BBL, we adapted
the model system for a time-shift setting. Here, enhanced proliferation and granzyme B expression
as well as reduced PD-1 expression on the T cell population demonstrated the benefit of
costimulation-assisted restimulation. Finally, the antitumor potential of this combinatorial
setting was confirmed in vivo in a lung metastasis mouse model. Thus, combinatorial approaches with
costimulatory antibody–ligand fusion proteins seem a promising strategy to be further investigated
for cancer immunotherapy.