Consecutive low doses of cyclophosphamide preferentially target Tregs and potentiate T cell responses induced by DNA PLG microparticle immunization.
Cyclophosphamide in combination with immunotherapeutic approaches preferentially impinges on T(reg) activity and allows for robust generation of T cell effectors. Reduced dosages of cyclophosphamide are necessary to restrict its cytotoxic effects to the negative regulatory cell populations while sparing effector lymphocytes. We investigated cyclophosphamide dosing in combination with ZYC300, a PLG-encapsulated plasmid DNA vaccine which encodes the cytochrome P450 family member, CYP1B1, a known human tumor-associated antigen. In mice, three consecutive, low doses of cyclophosphamide comprised a superior regimen in enhancing the magnitude, diversity of epitopes, and avidity to individual epitopes of specific T cell responses when compared to regimens that used either a single low or a single high dose. Consecutive low doses of cyclophosphamide predominantly targeted T(regs) while sparing overall T lymphocyte counts. Thus, we report the synergistic activity of pharmacologic T(reg) depletion with cyclophosphamide on quantitatively and qualitatively increasing T cell responses to a known human tumor-associated antigen.
Barbon
Christine M
CM
Dana-Farber Cancer Institute, Boston, MA, USA. ChristineM_Barbon@DFCI.harvard.edu
Yang
Min
M
Wands
Gregory D
GD
Ramesh
Radha
R
Slusher
Barbara S
BS
Hedley
Mary Lynne
ML
Luby
Thomas M
TM
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D003520:Cyclophosphamide / Q000276:immunology / Q000494:pharmacology*; D065633:Cytochrome P-450 CYP1B1; D004339:Drug Compounding; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D007114:Immunization; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology
D000951:Antigens, Neoplasm; D000939:Epitopes; D007166:Immunosuppressive Agents; D019444:Vaccines, DNA; D003520:Cyclophosphamide; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1