Abstract A14: Cellular immunotherapy for refractory hematological malignancies: Haploidentical donor lymphocyte infusions generate an allogeneic effect that targets leukemia.
Authors: John L. Reagan, Loren D. Fast, Martha Nevola, Andrew Schumacher, Kayla Rosati, Howard Safran, Matt I. Quesenberry, Eric P. Winer, James N. Butera, Peter J. Quesenberry
Journal: Clinical Cancer Research (2015)

Abstract Background/Objective: Allogeneic stem cell transplantation (allo-SCT) is an effective treatment modality for leukemia and lymphoma that exerts much of its therapeutic benefit via a graft versus tumor response. Its applicability is limited by toxicity from preconditioning chemoradiation and graft versus host disease. We present data from a Phase II IRB and FDA approved clinical trial in which haploidentical allogeneic cells are infused into patients with refractory hematologic malignancies without prior chemotherapy or radiation. The goal is to generate a robust allogeneic response created via donor cell rejection that breaks host tumor tolerance without the toxicity profile seen in allo-SCT. Methods: Eligible patients have refractory acute leukemias and aggressive systemic lymphomas without curative options. HLA haploidentical donors are identified then undergo leukapheresis without stem cell mobilization. 1-2x108 CD3+ cells/kg are infused unprocessed immediately following collection. Peripheral blood samples collected 1, 24, 48, 72 and 168 hours after infusion are examined for effector cell populations, stimulatory/inhibitory signals, and cytokine release profiles. Results: Three patients have been infused haploidentical cells. Two developed hyperpyrexia following treatment that persisted for 48 hours. One of three patients demonstrated a decrease in peripheral blood and bone marrow blast counts following therapy (Reduction in peripheral absolute blast count from 3900/uL to 1200/uL and bone marrow blasts from 43% to 21% four weeks post therapy). No Grade 3 or 4 toxicities or durable chimerism was seen. Host T cells demonstrated cytolytic effector molecule expression but little cytolytic activity, possibly secondary to rapid up-regulation of PD-1 and PD-1 ligands by host CD8+ cells and leukemia cells, respectively. Discussion: Haploidentical donor cellular infusions are well tolerated and demonstrate biological activity in relapsed leukemia. Lab correlative studies suggest potential future mechanisms to augment response involving PD-1 blockade. Our method provides a true bench to bedside approach utilizing adoptive immunotherapy created via a host allogeneic rejection response. Citation Format: John L. Reagan, Loren D. Fast, Martha Nevola, Andrew Schumacher, Kayla Rosati, Howard Safran, Matt I. Quesenberry, Eric P. Winer, James N. Butera, Peter J. Quesenberry. Cellular immunotherapy for refractory hematological malignancies: Haploidentical donor lymphocyte infusions generate an allogeneic effect that targets leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A14.