Abstract
BackgroundImmunotherapeutic protocols have focused on identification of stimuli that induce effective anti-leukemic immune responses. One potent immune stimulus is the encounter with allogeneic cells. Our group previously showed that the infusion of haploidentical donor white blood cells (1–2 × 108 CD3+ cells/kg) into patients with refractory hematological malignancies induced responses of varying magnitude in over half of the patients. Because donor cells were eliminated within 2 weeks in these patients, it is presumed that the responses of recipient lymphocytes were critically important in achieving prolonged anti-leukemic responses.MethodsThe role of patient CD3+ cells in anti-leukemic responses was examined by isolating peripheral blood mononuclear cells from newly diagnosed leukemic patients. Immunophenotyping was performed on these peripheral blood mononuclear cells. CD3+ cells were isolated from the peripheral blood mononuclear cells and tested for their ability to proliferate and lyse autologous leukemic cells when stimulated with unrelated allogeneic cells.ResultsAllostimulated CD3+ cells effectively generated cytolytic responses to autologous CD3-cells in 11/21 patients. Increased numbers of CD4+ cells expressing high levels of granzyme A, B and perforin and CD8+CD39+ cells were found in nonresponsive CD3+ cells.ConclusionsThese results indicate that CD3+ cells from leukemic patients are capable of generating anti-leukemic responses when stimulated with unrelated allogeneic cells. This model can be used to identify approaches using alloreactive responses by patient lymphocytes to enhance in vivo anti-leukemic responses.
Highlights
Immunotherapeutic protocols have focused on identification of stimuli that induce effective antileukemic immune responses
Allogeneic cells are one of the more potent stimuli of the immune system, as 100–1000 fold more cells respond to an allogeneic major histocompatibility complex (MHC) molecules than to a foreign peptide presented by self MHC molecules [1]
Alloreactivity is the driving force for deleterious responses such as graft-versus-host disease (GVHD) and organ rejection seen in transplantation, but is linked to beneficial graft versus leukemia (GVL) responses which has led to efforts to separate GVL
Summary
Immunotherapeutic protocols have focused on identification of stimuli that induce effective antileukemic immune responses. Within our group a nonengraftment donor leukocyte infusion protocol, in which infusion of large numbers of haploidentical cells at a dose of 1–2 × 108 CD3+ cells/kg into patients with refractory hematological malignancies, resulted in responses of varying magnitude in over half of the patients tested (14/26 overall responses with 5 complete responses) including three complete responses in patients with refractory acute myeloid leukemia (AML) [3]. These responses occurred in the absence of durable engraftment as donor cells were no longer detected within 2 weeks of infusion. We describe the ability of leukemic patient CD3+ lymphocytes to generate cytolytic responses against the syngeneic CD3-fraction, which includes leukemia cells, in vitro following stimulation with allogeneic donor peripheral blood mononuclear cells (PBMC)
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