title: Antibody-Drug Conjugates Bearing Pyrrolobenzodiazepine or Tubulysin Payloads Are Immunomodulatory and Synergize with Multiple Immunotherapies.
abstract: 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 (ADCS) conjugated with pyrrolobenzodiazepine dimer (PBD) or tubulysin payloads induce ICD, modulate the immune microenvironment, and could combine with immuno-oncology 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 versus immunodeficient mice, demonstrating a contribution of the immune system to the antitumor activity of these ADCs. ADCs also induced immunologic memory. In the CT26 model, depletion of CD8+T cells abrogated the activity of ADCs when used alone or in combination with a PD-L1 antibody, confirming a role for T cells in antitumor activity. Combinations of ADCs with immuno-oncology drugs, including PD-1 or PD-L1 antibodies, 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 ADC and ADC/immuno-oncology combinations. These results suggest that it may be possible to develop novel combinatorial therapies with PBD- and tubulysin-based ADC and immuno-oncology drugs that may increase clinical responses.Cancer Res; 77(10); 2686-98. ©2017 AACR.
authors.affiliation: MedImmune, Gaithersburg, Maryland. riosdoriaj@medimmune.com.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rios-Doria
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Jay
authors.initials: J
authors.lastname: Harper
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Raymond
authors.initials: R
authors.lastname: Rothstein
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Leslie
authors.initials: L
authors.lastname: Wetzel
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Jon
authors.initials: J
authors.lastname: Chesebrough
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Allison
authors.initials: A
authors.lastname: Marrero
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Cui
authors.initials: C
authors.lastname: Chen
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Strout
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Kathy
authors.initials: K
authors.lastname: Mulgrew
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Kelly
authors.initials: K
authors.lastname: McGlinchey
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Ryan
authors.initials: R
authors.lastname: Fleming
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Binyam
authors.initials: B
authors.lastname: Bezabeh
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: John
authors.initials: J
authors.lastname: Meekin
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: David
authors.initials: D
authors.lastname: Stewart
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Maureen
authors.initials: M
authors.lastname: Kennedy
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Philip
authors.initials: P
authors.lastname: Martin
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Andrew
authors.initials: A
authors.lastname: Buchanan
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Dimasi
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Emil
authors.initials: E
authors.lastname: Michelotti
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Robert
authors.initials: R
authors.lastname: Hollingsworth
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D015415:Biomarkers; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology*; D007156:Immunologic Memory; D016130:Immunophenotyping; D007167:Immunotherapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D015415:Biomarkers; D019496:Cancer Vaccines; D018796:Immunoconjugates; D007155:Immunologic Factors; D061026:Programmed Cell Death 1 Receptor; D011758:Pyrroles; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines