title: Three steps to breaking immune tolerance to lymphoma: a microparticle approach.
abstract: In situ immunization aims at generating antitumor immune responses through manipulating the tumor microenvironment. On the basis of recent advances in the understanding of antitumor immunity, we designed a three-step approach to in situ immunization to lymphoma: (i) inducing immunogenic tumor cell death with the chemotherapeutic drug doxorubicin. Doxorubicin enhances the expression of "eat-me" signals by dying tumor cells, facilitating their phagocytosis by dendritic cells (DC). Because of the vesicant activity of doxorubicin, microparticles made of biodegradable polymer poly(lactide-co-glycolide) or PLGA can safely deliver doxorubicin intratumorally and are effective vaccine adjuvants, (ii) enhancing T-cell activation using anti-OX40 and (iii) sustaining T-cell responses by checkpoint blockade using anti-CTLA-4. In vitro, doxorubicin microparticles were less cytotoxic to DCs than to B lymphoma cells, did not require internalization by tumor cells, and significantly enhanced phagocytosis of tumor cells by DCs as compared with soluble doxorubicin. In mice, this three-step therapy induced CD4- and CD8-dependent systemic immune responses that enhanced T-cell infiltration into distant tumors, leading to their eradication and significantly improving survival. Our findings demonstrate that systemic antitumor immune responses can be generated locally by three-step therapy and merit further investigation as an immunotherapy for patients with lymphoma.
authors: Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa.
authors: Amani
authors: A
authors: Makkouk
authors: Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa.
authors: Vijaya B
authors: VB
authors: Joshi
authors: Holden Comprehensive Cancer Center and Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors: Caitlin D
authors: CD
authors: Lemke
authors: Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa.
authors: Amaraporn
authors: A
authors: Wongrakpanich
authors: Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors: Alicia K
authors: AK
authors: Olivier
authors: Holden Comprehensive Cancer Center and Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors: Sue E
authors: SE
authors: Blackwell
authors: Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa. Holden Comprehensive Cancer Center and Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors: Aliasger K
authors: AK
authors: Salem
authors: Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa. Holden Comprehensive Cancer Center and Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa. george-weiner@uiowa.edu.
authors: George J
authors: GJ
authors: Weiner
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007167:Immunotherapy / Q000379:methods; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008223:Lymphoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008863:Microspheres; D009368:Neoplasm Transplantation; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D053262:Receptors, OX40 / Q000276:immunology; D012995:Solubility
chemical_list: D000276:Adjuvants, Immunologic; D000903:Antibiotics, Antineoplastic; D060908:CTLA-4 Antigen; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; D004317:Doxorubicin
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