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

doi:10.1073/pnas.132657799

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

^*Division of Oncology, Departments of Medicine and Genetics, Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8007, St. Louis, MO 63110-1093; and ^‡Aronex Pharmaceuticals, Inc., 8707 Technology Forest Place, The Woodlands, TX 77381-1191

Edited by Philip W. Majerus, Washington University School of Medicine, St. Louis, MO, and approved May 9, 2002 (received for review December 10, 2001)

Abstract

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 α (RARα) and RARα/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 × C3H F₁ (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.

Footnotes

↵ † Present address: Department of Medicine, University of Massachusetts, 55 Lake Avenue North, Worcester, MA 01605.
↵ § Present address: Dyax Corporation, One Kendall Square, Building 600, Suite 623, Cambridge, MA 02139.
↵ ¶ To whom reprint requests should be addressed. E-mail: timley{at}im.wustl.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

APL,

acute promyelocytic leukemia;

PML,

promyelocytic leukemia;

RARα,

retinoic acid receptor α;

ATRA,

all-trans-retinoic acid;

Lipo ATRA,

liposomally encapsulated all-trans-retinoic acid;

SCID,

severe combined immunodeficient;

AUC,

area under the concentration-time curve;

WBC,

white blood cell