title: Vaccination during myeloid cell depletion by cancer chemotherapy fosters robust T cell responses.
abstract: Therapeutic vaccination with human papillomavirus type 16 synthetic long peptides (HPV16-SLPs) results in T cell-mediated regression of HPV16-induced premalignant lesions but fails to install clinically effective immunity in patients with HPV16-positive cervical cancer. We explored whether HPV16-SLP vaccination can be combined with standard carboplatin and paclitaxel chemotherapy to improve immunity and which time point would be optimal for vaccination. This was studied in the HPV16 E6/E7-positive TC-1 mouse tumor model and in patients with advanced cervical cancer. In mice and patients, the presence of a progressing tumor was associated with abnormal frequencies of circulating myeloid cells. Treatment of TC-1-bearing mice with chemotherapy and therapeutic vaccination resulted in superior survival and was directly related to a chemotherapy-mediated altered composition of the myeloid cell population in the blood and tumor. Chemotherapy had no effect on tumor-specific T cell responses. In advanced cervical cancer patients, carboplatin-paclitaxel also normalized the abnormal numbers of circulating myeloid cells, and this was associated with increased T cell reactivity to recall antigens. The effect was most pronounced starting 2 weeks after the second cycle of chemotherapy, providing an optimal immunological window for vaccination. This was validated with a single dose of HPV16-SLP vaccine given in this time window. The resulting proliferative HPV16-specific T cell responses were unusually strong and were retained after all cycles of chemotherapy. In conclusion, carboplatin-paclitaxel therapy fosters vigorous vaccine-induced T cell responses when vaccination is given after chemotherapy and has reset the tumor-induced abnormal myeloid cell composition to normal values.
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
authors.forename: Marij J
authors.initials: MJ
authors.lastname: Welters
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
authors.forename: Tetje C
authors.initials: TC
authors.lastname: van der Sluis
authors.affiliation: Department of Gynecology, Leiden University Medical Center, 2300 RC Leiden, Netherlands. Centre for Human Drug Research, 2333 CL Leiden, Netherlands.
authors.forename: Hélène
authors.initials: H
authors.lastname: van Meir
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
authors.forename: Nikki M
authors.initials: NM
authors.lastname: Loof
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
authors.forename: Vanessa J
authors.initials: VJ
authors.lastname: van Ham
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
authors.forename: Suzanne
authors.initials: S
authors.lastname: van Duikeren
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
authors.forename: Saskia J
authors.initials: SJ
authors.lastname: Santegoets
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
authors.forename: Ramon
authors.initials: R
authors.lastname: Arens
authors.affiliation: Centre for Human Drug Research, 2333 CL Leiden, Netherlands.
authors.forename: Marieke L
authors.initials: ML
authors.lastname: de Kam
authors.affiliation: Centre for Human Drug Research, 2333 CL Leiden, Netherlands.
authors.forename: Adam F
authors.initials: AF
authors.lastname: Cohen
authors.affiliation: Department of Gynecology, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
authors.forename: Mariette I
authors.initials: MI
authors.lastname: van Poelgeest
authors.affiliation: Department of Gynecology, Academic Medical Center, 1100 DD Amsterdam, Netherlands.
authors.forename: Gemma G
authors.initials: GG
authors.lastname: Kenter
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
authors.forename: Judith R
authors.initials: JR
authors.lastname: Kroep
authors.affiliation: Centre for Human Drug Research, 2333 CL Leiden, Netherlands.
authors.forename: Jacobus
authors.initials: J
authors.lastname: Burggraaf
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, Netherlands. ISA Pharmaceuticals, 2333 CH Leiden, Netherlands.
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: Melief
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, 2300 RC Leiden, Netherlands. shvdburg@lumc.nl.
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002452:Cell Count; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D052162:Human papillomavirus 16 / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007109:Immunity / Q000187:drug effects; D007167:Immunotherapy; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology; D014611:Vaccination
chemical_list: D000970:Antineoplastic Agents