title: Protection from tumor recurrence following adoptive immunotherapy varies with host conditioning regimen despite initial regression of autochthonous murine brain tumors.
abstract: Adoptive T cell transfer (ACT) has achieved clinical success in treating established cancer, particularly in combination with lymphodepleting regimens. Our group previously demonstrated that ACT following whole-body irradiation (WBI) promotes high-level T cell accumulation, regression of established brain tumors, and long-term protection from tumor recurrence in a mouse model of SV40 T antigen-induced choroid plexus tumors. Here we asked whether an approach that can promote strong donor T-cell responses in the absence of WBI might also produce this dramatic and durable tumor elimination following ACT. Agonist anti-CD40 antibody can enhance antigen-specific CD8(+) T-cell responses and has shown clinical efficacy as a monotherapy in the setting of cancer. We show that anti-CD40 conditioning promotes rapid accumulation of tumor-specific donor CD8(+) T cells in the brain and regression of autochthonous T antigen-induced choroid plexus tumors, similar to WBI. Despite a significant increase in the lifespan, tumors eventually recurred in anti-CD40-conditioned mice coincident with loss of T-cell persistence from both the brain and lymphoid organs. Depletion of CD8(+) T cells from the peripheral lymphoid organs of WBI-conditioned recipients failed to promote tumor recurrence, but donor cells persisted in the brains long-term in CD8-depleted mice. These results demonstrate that anti-CD40 conditioning effectively enhances ACT-mediated acute elimination of autochthonous tumors, but suggest that mechanisms associated with WBI conditioning, such as the induction of long-lived T cells, may be critical for protection from tumor recurrence.
authors.affiliation: Department of Microbiology and Immunology, Penn State Hershey College of Medicine, 500 University Drive, H107, Hershey, PA, 17033, USA.
authors.forename: Eugene M
authors.initials: EM
authors.lastname: Cozza
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Cooper
authors.forename: Lynn R
authors.initials: LR
authors.lastname: Budgeon
authors.forename: Neil D
authors.initials: ND
authors.lastname: Christensen
authors.forename: Todd D
authors.initials: TD
authors.lastname: Schell
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D001932:Brain Neoplasms / Q000276:immunology* / Q000532:radiotherapy / Q000628:therapy*; D019013:CD40 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D016019:Survival Analysis; D014916:Whole-Body Irradiation
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D007074:Immunoglobulin G