Abstract
The potent clinical responses seen in patients with chronic myeloid leukemia (CML) after administration of donor-specific lymphocytes, as well as the correlation between the presence of antigen specific T cells and prolonged remission in these patients, suggests a role for the immunological control of CML. Here we propose Aldara™, a clinically used formulation of imiquimod, as an agent for augmenting immune responses to CML antigens. Our proposition is based upon 3 tenets: 1) Endogenous dendritic cells (DC) of CML patients, which are known to be derived from the malignant clone, express and present various leukemic antigens; 2) CML-antigen reactive T cell clones exist in the patient but in many situations are ineffectively stimulated to cause significant hematological responses; and 3) Antigen presentation by mature, activated DC, which endogenously express CML-antigens may endow the pre-existing ineffective T cell responses with ability to control CML progression. The practical use of Aldara™ as a localized activator of DC in the context of present day leukemic therapeutics, as well as various properties of this unique immune modulator will be discussed.
Highlights
Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by an indolent chronic phase during which immature myeloid cells increase in the peripheral blood and bone marrow, followed by an accelerated phase, associated with resistance to standard therapies, and terminates in blast crisis where undifferentiated blasts damage vital organs, leading in death
This concept has been demonstrated clinically through the use of GM-CSF administration to expand endogenous DC numbers followed by donor lymphocyte infusion, resulting in a positive impact on patient survival that was associated with increased anti-leukemic response [81], which was believed to be due to enhanced presentation of leukemic antigens from DC
We argue that numerous CML antigens exist that would not be present in leukemia-derived DC, BCR-ABL, which is present, is known to be clinically relevant based on responses observed in patients immunized with BCR-ABL-derived peptides [17,87]
Summary
Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by an indolent chronic phase during which immature myeloid cells increase in the peripheral blood and bone marrow, followed by an accelerated phase, associated with resistance to standard therapies, and terminates in blast crisis where undifferentiated blasts damage vital organs, leading in death. CML is different than almost any other cancer in that DC immunotherapy would not require the pulsing of DC with exogenous antigens, since CML DC endogenously express BCR-ABL immunogenic peptides at sufficient concentrations to stimulate a T cell response [80] This concept has been demonstrated clinically through the use of GM-CSF administration to expand endogenous DC numbers followed by donor lymphocyte infusion, resulting in a positive impact on patient survival that was associated with increased anti-leukemic response [81], which was believed to be due to enhanced presentation of leukemic antigens from DC. CML-directed responses do not crossreact with nonmalignant progenitor cells
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