Adaptive immunity cooperates with liposomal all-trans-retinoic acid (ATRA) to facilitate long-term molecular remissions in mice with acute promyelocytic leukemia.
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 (RAR alpha) and RAR alpha/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.
Westervelt
Peter
P
Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8007, St. Louis, MO 63110-1093, USA.
Pollock
Jessica L
JL
Oldfather
Kristie M
KM
Walter
Matthew J
MJ
Ma
Margaret K
MK
Williams
Anthony
A
DiPersio
John F
JF
Ley
Timothy J
TJ
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D007121:Immunocompetence; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008081:Liposomes; D051379:Mice; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010087:Oxides / Q000008:administration & dosage / Q000493:pharmacokinetics; D014212:Tretinoin / Q000008:administration & dosage* / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D001152:Arsenicals; D008081:Liposomes; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D010087:Oxides; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D000077237:Arsenic Trioxide