title: Myeloablative temozolomide enhances CD8⁺ T-cell responses to vaccine and is required for efficacy against brain tumors in mice.
abstract: Temozolomide (TMZ) is an alkylating agent shown to prolong survival in patients with high grade glioma and is routinely used to treat melanoma brain metastases. A prominent side effect of TMZ is induction of profound lymphopenia, which some suggest may be incompatible with immunotherapy. Conversely, it has been proposed that recovery from chemotherapy-induced lymphopenia may actually be exploited to potentiate T-cell responses. Here, we report the first demonstration of TMZ as an immune host-conditioning regimen in an experimental model of brain tumor and examine its impact on antitumor efficacy of a well-characterized peptide vaccine. Our results show that high-dose, myeloablative (MA) TMZ resulted in markedly reduced CD4(+), CD8(+) T-cell and CD4(+)Foxp3(+) TReg counts. Adoptive transfer of naïve CD8(+) T cells and vaccination in this setting led to an approximately 70-fold expansion of antigen-specific CD8(+) T cells over controls. Ex vivo analysis of effector functions revealed significantly enhanced levels of pro-inflammatory cytokine secretion from mice receiving MA TMZ when compared to those treated with a lower lymphodepletive, non-myeloablative (NMA) dose. Importantly, MA TMZ, but not NMA TMZ was uniquely associated with an elevation of endogenous IL-2 serum levels, which we also show was required for optimal T-cell expansion. Accordingly, in a murine model of established intracerebral tumor, vaccination-induced immunity in the setting of MA TMZ-but not lymphodepletive, NMA TMZ-led to significantly prolonged survival. Overall, these results may be used to leverage the side-effects of a clinically-approved chemotherapy and should be considered in future study design of immune-based treatments for brain tumors.
authors.affiliation: Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Sanchez-Perez
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Choi
authors.forename: Gary E
authors.initials: GE
authors.lastname: Archer
authors.forename: Xiuyu
authors.initials: X
authors.lastname: Cui
authors.forename: Catherine
authors.initials: C
authors.lastname: Flores
authors.forename: Laura A
authors.initials: LA
authors.lastname: Johnson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schmittling
authors.forename: David
authors.initials: D
authors.lastname: Snyder
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Duane A
authors.initials: DA
authors.lastname: Mitchell
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D003606:Dacarbazine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D007167:Immunotherapy; D007376:Interleukin-2 / Q000097:blood / Q000494:pharmacology; D008212:Lymphocyte Depletion; D008231:Lymphopenia / Q000139:chemically induced; D051379:Mice; D008822:Mice, Transgenic; D000077204:Temozolomide; D022223:Vaccines, Subunit / Q000276:immunology
chemical_list: D000941:Antigens; D018906:Antineoplastic Agents, Alkylating; D019496:Cancer Vaccines; D007376:Interleukin-2; D022223:Vaccines, Subunit; D003606:Dacarbazine; D000077204:Temozolomide