Immunogenic cell death (ICD) is the process by which certain cytotoxic drugs induce apoptosis of tumor cells in a manner that stimulates the immune system. In this study, we investigated whether antibody-drug conjugates (ADC) conjugated with pyrrolobenzodiazepine dimer (PBD) or tubulysin payloads induce ICD, modulate the immune microenvironment, and could combine with IO drugs to enhance antitumor activity. We show that these payloads on their own induced an immune response that prevented the growth of tumors following subsequent tumor cell challenge. ADC had greater antitumor activity in immunocompetent versus immunodeficient mice, demonstrating a contribution of the immune system to the antitumor activity of ADC. ADC also induced immunological memory. In the CT26 model, depletion of CD8+ T cells abrogated the activity of ADC when used alone or in combination with a PD-L1 antibody, confirming a role for T cells in antitumor activity. Combinations of ADC with IO drugs, including PD-1 orPD-L1 antibodies, OX40 ligand, or GITR ligand fusion proteins produced synergistic antitumor responses. Importantly, synergy was observed in some cases with suboptimal doses of ADC, potentially providing an approach to achieve potent antitumor responses while minimizing ADC-induced toxicity. Immunophenotyping studies in different tumor models revealed broad immunomodulation of lymphoid and myeloid cells by ADC and ADC/IO combinations. These results suggest that it may be possible to develop novel combinatorial therapies with PBD- and tubulysin-based ADC and IO drugs that may increase clinical responses.
- Received October 21, 2016.
- Revision received January 31, 2017.
- Accepted March 2, 2017.
- Copyright ©2017, American Association for Cancer Research.