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Combining ADCs with Immuno-Oncology Agents

  • Philipp Müller
  • Jonathan Rios-Doria
  • Jay Harper
  • Anthony Cao
Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

Immuno-oncology (IO) has emerged as one of the most promising approaches to improve the therapeutic efficacy and durability of clinical responses in cancer patients. However, despite the clinical breakthroughs achieved with immuno-therapies, such as checkpoint blockade, the overall proportion of patients experiencing durable responses to single agent immuno-therapy remains relatively small. Therefore, the real promise for most cancer patients does not lie in monotherapeutic approaches but in synergistic combination therapies, which combine the best of IO with the immune-promoting/supporting properties of other therapeutic modalities. The latter help to breach physical barriers, to overcome immunosuppressive networks within the tumor microenvironment and improve immune cell infiltration into tumors.

Certain classes of cytotoxic compounds as well as radiation have been shown to induce immunogenic cell death (ICD), which leads to potent stimulation of effector T-cell activation as well as their recruitment into tumors. It has been recently demonstrated that some ADC payloads are also able to elicit ICD. Furthermore, several cytotoxic warheads used in ADCs can directly induce dendritic cell activation and maturation. These previously unknown immune-stimulatory activities of ADCs therefore have the potential to boost anti-tumor immunity and indeed the synergistic activity of various ADC/IO combinations has been observed in preclinical tumor models. These preclinical data have supported the clinical evaluation of ADC/IO combinatorial approaches.

This chapter summarizes the current scientific knowledge on the immunomodulatory properties of cytotoxic warheads used in ADCs, the underlying molecular mechanisms and immunological as well as therapeutic benefits of combination regimens with immuno-therapies. It further provides an overview of the current clinical landscape of more than 20 clinical trials evaluating the therapeutic benefit of ADC/IO combinations for cancer patients.

Keywords

Adcetris ADC ADC-IO combinations Ado-trastuzumab emtansine Ansamitocin P3 Antibody drug conjugate Antigen presentation Auristatin Atezolizumab ATP Brentuximab vedotin Calreticulin CD11c CD27 CD39 CD4 CD8 CD73 CD86 CD91 Cell death Checkpoint inhibitors Clinical development Clinical trials Combination therapy Combo CRT CT26 CTL-Cytotoxic lymphocyte CTLA-4 DCs Dendritic cells Dendritic cell activation Dendritic cell maturation Depolymerization Destabilization DM-1 Dolastatin EphA2 ER stress Fo5 FoxP3 GITR GITRL Her2 HMGB1 NHL Non-Hodgkin Lymphoma ICD ICD hallmarks IFN IGF1R Immunogenic cell death Immuno-oncology Immunotherapy Interferon Ipilimumab Kadcyla Keytruda MCA205 MHC-I MHC-II Microtubule Depolymerization Microtubule Destabilization MMAE MyD88 Nivolumab Opdivo OX40 PBD PD-1 PD-L1 Pembrolizumab Regulatory T cell Synergy TAA T cells T cell agonists T cell activation T-DM1 Therapeutic index Therapy TLR-4 Trastuzumab emtansine Treg Tubulysin Tumor Tumor associated antigen Varlilumab Warhead Yervoy 

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Philipp Müller
    • 1
  • Jonathan Rios-Doria
    • 2
    • 3
  • Jay Harper
    • 2
  • Anthony Cao
    • 4
  1. 1.Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Cancer Immunology & Immune ModulationBiberach an der RissGermany
  2. 2.MedImmuneGaithersburgUSA
  3. 3.IncyteWilmingtonUSA
  4. 4.Seattle Genetics, IncBothellUSA

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