Abstract
Immune checkpoint blockers have dramatically improved the chances of survival in patients with metastatic cancer, but only a subset of the patients respond to treatment. Search for novel targets that can improve the responder rates and overcome the limitations of adverse events commonly seen with combination therapies, like PD-1 plus CTLA-4 blockade and PD-1/PD-L1 plus chemotherapy, led to the development of monoclonal antibodies blocking T-cell immunoglobulin and ITIM domain (TIGIT), a inhibitory checkpoint receptor expressed on activated T cells and NK cells. The strategy showed potential in pre-clinical and early clinical studies, and 5 molecules are now in advanced stages of evaluation (phase II and above). This review aims to provide an overview of clinical development of anti-TIGIT antibodies and describes the factors considered and thought process during early clinical development. Critical aspects that can decide the fate of clinical programs, such as origin of the antibody, Ig isotype, FCγR binding, and the dose as well as dosing schedule, are discussed along with the summary of available efficacy and safety data from clinical studies and the challenges in the development of anti-TIGIT antibodies, such as identifying patients who can benefit from therapy and getting payer coverage.
Highlights
Dose-limiting toxicities were not recorded during monotherapy or in combination with anti-Programmed Cell-Death 1 (PD-1) antibody for any of the anti-T-cell immunoglobulin and ITIM domain (TIGIT) antibodies in clinical development, indicating molecules against this target have broad therapeutic index
Clinical activity observed after anti-TIGIT antibody monotherapy was minimal to none, indicating combination therapy with anti-PD1 or PD-L1 or other agents is needed
Combination therapies, like PD-1 plus Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade and PD-1/PD-L1 plus chemotherapy, have increased the responder rates, but they are limited by increased incidence of serious, dose-limiting, adverse events, and a decent proportion of patients still do not respond to combination therapy
Summary
Discovery of checkpoints of T-cell activation and development of monoclonal antibodies targeting the checkpoints dramatically changed the outcomes of immunotherapy [6,7,8,9,10,11,12]
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