title: Dual-specific Chimeric Antigen Receptor T Cells and an Indirect Vaccine Eradicate a Variety of Large Solid Tumors in an Immunocompetent, Self-antigen Setting.
abstract: Purpose:While adoptive transfer of T cells bearing a chimeric antigen receptor (CAR) can eliminate substantial burdens of some leukemias, the ultimate challenge remains the eradication of large solid tumors for most cancers. We aimed to develop an immunotherapy approach effective against large tumors in an immunocompetent, self-antigen preclinical mouse model.Experimental Design:In this study, we generated dual-specific T cells expressing both a CAR specific for Her2 and a TCR specific for the melanocyte protein (gp100). We used a regimen of adoptive cell transfer incorporating vaccination (ACTIV), with recombinant vaccinia virus expressing gp100, to treat a range of tumors including orthotopic breast tumors and large liver tumors.Results:ACTIV therapy induced durable complete remission of a variety of Her2+tumors, some in excess of 150 mm2, in immunocompetent mice expressing Her2 in normal tissues, including the breast and brain. Vaccinia virus induced extensive proliferation of T cells, leading to massive infiltration of T cells into tumors. Durable tumor responses required the chemokine receptor CXCR3 and exogenous IL2, but were independent of IFNγ. Mice were resistant to tumor rechallenge, indicating immune memory involving epitope spreading. Evidence of limited neurologic toxicity was observed, associated with infiltration of cerebellum by T cells, but was only transient.Conclusions:This study supports a view that it is possible to design a highly effective combination immunotherapy for solid cancers, with acceptable transient toxicity, even when the target antigen is also expressed in vital tissues.Clin Cancer Res; 23(10); 2478-90. ©2016 AACR.
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia. michael.kershaw@petermac.org clare.slaney@petermac.org.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Clare Y
authors.initials: CY
authors.lastname: Slaney
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Bianca
authors.initials: B
authors.lastname: von Scheidt
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Davenport
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Beavis
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Westwood
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Sherly
authors.initials: S
authors.lastname: Mardiana
authors.affiliation: John Curtin School of Medical Research, Australian National University, Canberra, Australia.
authors.forename: David C
authors.initials: DC
authors.lastname: Tscharke
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ellis
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: H Miles
authors.initials: HM
authors.lastname: Prince
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.affiliation: Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Michele W
authors.initials: MW
authors.lastname: Teng
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Aesha
authors.initials: A
authors.lastname: Ali
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, Maryland.
authors.forename: Zhiya
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, Maryland.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, Maryland.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Neeson
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.|Department of Immunology, Monash University, Clayton, Australia.
authors.forename: Phillip K
authors.initials: PK
authors.lastname: Darcy
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia. michael.kershaw@petermac.org clare.slaney@petermac.org.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.|Department of Immunology, Monash University, Clayton, Australia.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kershaw
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000008:administration & dosage / Q000276:immunology; D001932:Brain Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000008:administration & dosage / Q000276:immunology; D012074:Remission Induction; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology; D058951:gp100 Melanoma Antigen / Q000235:genetics / Q000276:immunology*
chemical_list: D001324:Autoantigens; D019496:Cancer Vaccines; D007371:Interferon-gamma; D018719:Erb-b2 Receptor Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; D058951:gp100 Melanoma Antigen; C508053:ERBB2 protein, human