Consecutive low doses of cyclophosphamide preferentially target Tregs and potentiate T cell responses induced by DNA PLG microparticle immunization

Dana-Farber Cancer Institute, Boston, MA, USA.
Cellular Immunology (Impact Factor: 1.92). 02/2010; 262(2):150-61. DOI: 10.1016/j.cellimm.2010.02.007
Source: PubMed


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.

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Available from: Christine M Barbon, Jul 03, 2014
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    • "Cord blood Tregs have been shown to be predominantly of the CD45RA + CD45RO − naïve phenotype in several studies (Kanegane et al., 1991; Wing et al., 2002; Takahata et al., 2004; Ly et al., 2009; Flanagan et al., 2010). Other phenotypic differences between cord and adult Tregs include the observation that CB Tregs are mostly CD27 + and thus at an earlier differentiation state than their mothers; they have a lower apoptotic potential as evidenced by lower CD95/Fas expression than their mothers; and less CD62L suggesting less of a Treg CM lymph node homing phenotype (Flanagan et al., 2010). CB Tregs also express less CCR6 than their matched mothers, which is the chemokine receptor that characterizes the Th17-and Th22-like Tregs (Duhen et al., 2012). "
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    • "Higher, cytotoxic doses of CPA impact all of the T-lymphocyte populations, resulting not only in reduced Treg counts but also reduced CD4+, CD8+, and total splenocyte counts [29,33]. Thus, a cytotoxic dose of CPA can impair the immune response to tumor-associated antigens [29]. These observations are consistent with Motoyoshi et al. who showed that low-dose CPA produced an antitumor immune response by selectively depleting Tregs in immunocompetent mice, while the effects of high-dose CPA were attributable solely to its cytotoxic effects [33]. "
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