Adaptive immunity cooperates with liposomal all-trans-retinoic acid (ATRA) to facilitate long-term molecular remissions in mice with acute promyelocytic leukemia

被引:40
作者
Westervelt, P
Pollock, JL
Oldfather, KM
Walter, MJ
Ma, MK
Williams, A
DiPersio, JF
Ley, TJ
机构
[1] Washington Univ, Sch Med, Div Oncol, Dept Med,Siteman Canc Ctr, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Div Oncol, Dept Geneet,Siteman Canc Ctr, St Louis, MO 63110 USA
[3] Aronex Pharmaceut Inc, The Woodlands, TX 77381 USA
关键词
D O I
10.1073/pnas.132657799
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
We previously developed a murine model of acute promyelocytic leukemia (APL) by using human cathepsin G gene regulatory elements to direct the expression of promyelocytic leukemia (PML)/retinoic acid receptor alpha (RARalpha) and RARalpha/PML fusion cDNAs to the early myeloid compartment of transgenic mice. To study the efficacy of noncytotoxic therapy in this animal model, cohorts of naive immunocompetent mice were inoculated with primary murine APL cells from a frozen tumor bank. Arsenic trioxide and liposomally encapsulated all-trans-retinoic acid (Lipo ATRA), alone or in combination, were administered for 21 days by i.p. injection using doses that yielded plasma levels similar to those observed in human APL patients treated with these agents. Lipo ATRA was highly effective in inducing durable molecular remissions in immunocompetent mice [C57BL/6 x C3H F-1 (B6C3HF1)]; arsenic therapy was much less effective, and did not clearly synergize with Lipo ATRA to increase the remission rate in immunocompetent mice. The survival of Lipo ATRA-treated severe combined immunodeficient (SCID) animals (lacking functional T and B cells) was inferior to that of immunocompetent B6C3HF1 recipients (40% vs. 88% survival at 1 y, P < 0.001). These data suggest that adaptive immunity cooperates with pharmacologic therapy to induce or maintain remissions in murine APL. It also implies that immunosuppressive anti-leukemia therapies could paradoxically blunt effective anti-leukemia immune responses that are important for clearing small numbers of residual tumor cells after chemotherapy-mediated cytoreduction.
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页码:9468 / 9473
页数:6
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