Improving CD3 bispecific antibody therapy for solid cancer

Abstract

The work in this thesis focuses on overcoming obstacles for successful treatment of solid cancers using CD3 bispecific antibody therapy. These antibodies bind with one arm to a tumor antigen on the tumor cell and with the other to CD3e on the T cell, resulting in T-cell activation and subsequent tumor cell killing irrespective of the specificity of the T cell. This therapy is successfully employed to treat haematological malignancies, but results against solid tumors have been limited thus far due to several additional obstacles including more severe on-target-off-tumor toxicities, lack of T-cell infiltration and impaired T-cell functionality due to the immunosuppressive tumor microenvironment. This thesis used several combination approaches with the aim to overcome those additional hurdles. The most prominent finding is that application of therapeutic vaccines, designed to raise T-cell responses, results in profound intratumoral T cell infiltration and a proinflammatory tumor microenvironment both of which empower the therapeutic efficacy of the subsequently injected CD3 bispecific antibody. Other notable findings are that this enhanced therapeutic efficacy is dependent on macrophages, which are activated by the combination treatment, and that the use of tumor-specific vaccines also confers protection against tumor rechallenge as a surrogate for late relapse.