title: Late administration of murine CTLA-4 blockade prolongs CD8-mediated anti-tumor effects following stimulatory cancer immunotherapy.
abstract: We have demonstrated that immunostimulatory therapies such as interleukin-2 (IL-2) and anti-CD40 (αCD40) can be combined to deliver synergistic anti-tumor effects. While this strategy has shown success, efficacy varies depending on a number of factors including tumor type and severe toxicities can be seen. We sought to determine whether blockade of negative regulators such as cytotoxic T lymphocyte antigen-4 (CTLA-4) could simultaneously prolong CD8(+) T cell responses and augment T cell anti-tumor effects. We devised a regimen in which anti-CTLA-4 was administered late so as to delay contraction and minimize toxicities. This late administration both enhanced and prolonged CD8 T cell activation without the need for additional IL-2. The quality of the T cell response was improved with increased frequency of effector/effector memory phenotype cells along with improved lytic ability and bystander expansion. This enhanced CD8 response translated to improved anti-tumor responses both at the primary and metastatic sites. Importantly, toxicities were not exacerbated with combination. This study provides a platform for rational design of immunotherapy combinations to maximize anti-tumor immunity while minimizing toxicities.
authors.affiliation: Department of Dermatology, University of California, Davis, School of Medicine, IRC Building Rm 1630, 2921 Stockton Blvd., Sacramento, CA, 95817, USA.
authors.forename: Gail D
authors.initials: GD
authors.lastname: Sckisel
authors.affiliation: Department of Dermatology, University of California, Davis, School of Medicine, IRC Building Rm 1630, 2921 Stockton Blvd., Sacramento, CA, 95817, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Mirsoian
authors.affiliation: Department of Dermatology, University of California, Davis, School of Medicine, IRC Building Rm 1630, 2921 Stockton Blvd., Sacramento, CA, 95817, USA.
authors.forename: Myriam N
authors.initials: MN
authors.lastname: Bouchlaka
authors.affiliation: Department of Dermatology, University of California, Davis, School of Medicine, IRC Building Rm 1630, 2921 Stockton Blvd., Sacramento, CA, 95817, USA.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Tietze
authors.affiliation: Department of Pathology, University of California, School of Medicine, Sacramento, CA, USA.
authors.forename: Mingyi
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, USA.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Department of Dermatology, University of California, Davis, School of Medicine, IRC Building Rm 1630, 2921 Stockton Blvd., Sacramento, CA, 95817, USA. wmjmurphy@ucdavis.edu.|Department of Internal Medicine, University of California, Davis, School of Medicine, Sacramento, CA, USA. wmjmurphy@ucdavis.edu.
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
mesh_terms: D000818:Animals; D016827:CD8 Antigens / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: C499839:CD40Ig protein, recombinant; D016827:CD8 Antigens; D060908:CTLA-4 Antigen; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins
keywords: Anti-CTLA-4; Bystander activation; Checkpoint blockade; Immunotherapy; Toxicities