Dissecting the use of recipient alloreactive responses to achieve anti-leukemic effect

Abstract

Abstract Harnessing alloreactive responses to incur anti-leukemic effects has focused on the donor lymphocyte response directed toward recipient antigens. Limited studies have examined the anti-leukemic potential of recipient alloreactive responses to donor cell antigens. An example is the infusion of large numbers of haploidentical, G-CSF mobilized, donor T cells (1 – 2 × 108 CD3+ cells/kg) into patients with refractory hematological malignancies who had received100 cGy total body irradiation prior to infusion. Strong recipient immune responses were generated capable of eliminating the donor cells within two weeks (thereby preventing GVHD) with side effects of high fever (104°F), malaise, rash, and diarrhea. More than half of these patients also generated responses to the hematological malignancies(14/26, 9 major), including some complete remissions. The protocol was modified in the reopened clinical trial by elimination of both the G-CSF mobilization of donor cells and the recipient 100 cGy total body irradiation. These patients exhibited milder, self-resolving fevers and limited anti-leukemic responses (1/5 with transient response). Analysis of blood samples obtained at several different timepoints after infusion revealed diminished IL-6 levels. Increased levels of plasma IL-2 and granzyme B and increased expression of granzyme B and PD-1 by activated recipient T cells correlated with elimination of donor cells. Increased expression of PD-1 ligands on leukemic cells provides one explanation for the lack of anti-leukemic response. These results indicate that appropriate manipulation of both donor cells and patients in this protocol should improve the anti-leukemic responses of recipient lymphocytes.