Curing tumor-bearing mice by shifting a Th2 to a Th1 anti-tumor response

Issue title: Agonist Antibodies

Guest editors: Michael Steinitz

Article type: Research Article

Authors: Hellstrom, Karl Erik^* | Dai, Min | Hellstrom, Ingegerd

Affiliations: Department of Pathology, University of Washington, Harborview Medical Center, Seattle, WA 98104, USA

Correspondence: [*] Corresponding author: Karl Erik Hellstrom, Department of Pathology, University of Washington, Harborview Medical Center, 300 9^th Ave, R{&}T Building Rm706A, Seattle, WA 98104, USA. Tel.: +1 206 897 5908; E-mail:hellsk@uw.edu

Abstract: Over the past several years remarkable therapeutic responses have been obtained with immunomodulatory monoclonal antibodies (mAbs), both in mice \cite{10,18,20,48,54,61} and human cancer patients \cite{1,3,14,28,30,39,80}. However, complete regressions and cures are infrequent and not predictable and some tumor types respond much worse than others. As an attempt to increase curability, we have investigated in mouse models the therapeutic efficacy of several mAb combinations, focusing on anti-PD-1/CTLA-4/CD137 and anti-PD-1/CTLA-4/CD137/CD19, and we have also combined mAbs with the chemotherapeutic drug cisplatin. Our data demonstrate an important contribution of anti-CD19 mAb to therapeutic efficacy, they show that intratumoral delivery of the mAbs is therapeutically more effective than systemic delivery, and that there is synergy when the mAbs are combined with cisplatin. In an attempt to improve predictability, we developed an in vitro model that may also be employed to search for novel immunomodulatory agents and combinations. This article reviews our data and discusses what is known about the underlying mechanisms.

Keywords: Tumor immunotherapy, immunomodulatory antibody, checkpoint inhibitors, mouse models, immunosuppression, autoimmunity

DOI: 10.3233/HAB-160309

Journal: Human Antibodies, vol. 25, no. 3-4, pp. 147-153, 2017