Combining antibody-drug conjugates with immunotherapy in solid tumors: current landscape and future perspectives

Antibody-drug conjugates (ADCs) and immunotherapy have prompted a revolution in the treatment of cancer. However, only a limited fraction of patients obtained a long-term benefit; consequently, combination studies have become a central focus of the current preclinical and clinical research in oncology. A strong biological rationale supports the investigation of combining ADCs with immunotherapy to overcome the occurrence of resistance and improve patient outcomes. ADCs interact with cancer and immune cells by eliciting mechanisms such as immunogenic cell death, antibody-dependent cell-mediated cytotoxicity and dendritic cell activation, ultimately providing potential synergism with immunotherapy. Indeed, ADCs induce tumor-specific adaptive immunity, increasing the infiltration of T cells into the tumor microenvironment, whereas immune-checkpoint inhibitors reinvigorate exhausted T cells, enhancing antitumor immune responses. In light of the promising preclinical data, several clinical trials are currently underway in multiple tumor types to evaluate the safety and activity of combination regimens. Initial evidence from early phase clinical trials has already reported encouraging signals. This review focuses on the combination of ADCs and immunotherapy, highlighting the key mechanisms underlying the synergistic effect and providing an overview of the available clinical evidence in solid tumors. In addition, opportunities to optimize the combination are explored, such as defining the optimal dose, balancing the risks and benefits of dose modifications, and the possibility of developing novel immunoconjugates.