title: Curing tumor-bearing mice by shifting a Th2 to a Th1 anti-tumor response.
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.
authors.forename: Karl Erik
authors.initials: KE
authors.lastname: Hellstrom
authors.forename: Min
authors.initials: M
authors.lastname: Dai
authors.forename: Ingegerd
authors.initials: I
authors.lastname: Hellstrom
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D002945:Cisplatin / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology
chemical_list: D018941:Antigens, CD19; D000074322:Antineoplastic Agents, Immunological; C000604812:CD19 antigen, mouse; D060908:CTLA-4 Antigen; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D002945:Cisplatin
keywords: Tumor immunotherapy; autoimmunity; checkpoint inhibitors; immunomodulatory antibody; immunosuppression; mouse models