Abstract 4596: Antibody-drug conjugates bearing pyrrolobenzodiazepine or tubulysin payloads alter the tumor immune microenvironment and synergize with multiple immunotherapies
| Autor: | Binyam Bezabeh, Robert E. Hollingsworth, Raymond Rothstein, Kathy Mulgrew, Ryan Fleming, Jonathan Rios-Doria, Andrew Buchanan, Emil Michelotti, David Stewart, Jay Harper, Jon Chesebrough, Allison M. Marrero, Philip Martin, Leslie Wetzel, John Meekin, Maureen Kennedy, Nazzareno Dimasi, Patrick Strout, Cui Chen, Kelly McGlinchey |
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| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Cancer Research. 77:4596-4596 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | 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 ADCs conjugated with pyrrolobenzodiazepine dimer (PBD) or tubulysin payloads induced ICD, modulated 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. ADCs had greater antitumor activity in immunocompetent vs. immunodeficient mice, demonstrating a contribution of the immune system to the antitumor activity of these ADCs. These ADCs also induced immunological memory. In the CT26 model, depletion of CD8+ T cells abrogated the activity of these ADCs when used alone or in combination with a PD-L1 antibody, confirming a role for T cells in the antitumor activity. Combinations of ADCs in different tumor models with IO drugs including PD-1 or PD-L1 antibodies, or OX40 ligand or GITR ligand fusion proteins produced synergistic antitumor responses. Importantly, synergy was observed in some cases with suboptimal doses of ADCs, 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 ADCs and ADC/IO combinations. These results suggest that it may be possible to develop novel combinatorial therapies with PBD- and tubulysin-based ADCs and IO drugs that may increase clinical responses. Citation Format: Jonathan Rios-Doria, Jay Harper, Raymond Rothstein, Leslie Wetzel, Jon Chesebrough, Allison Marrero, Cui Chen, Patrick Strout, Kathy Mulgrew, Kelly McGlinchey, Ryan Fleming, Binyam Bezabeh, John Meekin, David Stewart, Maureen Kennedy, Philip Martin, Andrew Buchanan, Nazzareno Dimasi, Emil Michelotti, Robert Hollingsworth. Antibody-drug conjugates bearing pyrrolobenzodiazepine or tubulysin payloads alter the tumor immune microenvironment and synergize with multiple immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4596. doi:10.1158/1538-7445.AM2017-4596 |
| Databáze: | OpenAIRE |
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