BCR-ABL–specific T-cell therapy in Ph+ ALL patients on tyrosine-kinase inhibitors

Abstract

Although the emergence of bone marrow (BM)-resident ^p190BCR-ABL-specific T lymphocytes has been correlated with hematologic and cytogenetic remissions in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL) undergoing maintenance tyrosine-kinase inhibitor treatment, little is known about the possibility of culturing these cells ex vivo and using them in T-cell therapy strategies. We investigated the feasibility of expanding/priming ^p190BCR-ABL-specific T cells in vitro by stimulation with dendritic cells pulsed with ^p190BCR-ABL peptides derived from the BCR-ABL junctional region and alternative splicing, and of adoptively administering them to patients with relapsed disease. We report on the feasibility of producing clinical-grade BCR-ABL-specific cytotoxic T lymphocytes (CTLs), endowed with antileukemia activity, from Ph⁺ ALL patients and healthy donors. We treated 3 patients with Ph⁺ ALL with autologous or allogeneic ^p190BCR-ABL-specific CTLs. No postinfusion toxicity was observed, except for a grade II skin graft-versus-host disease in the patient treated for hematologic relapse. All patients achieved a molecular or hematologic complete remission (CR) after T-cell therapy, upon emergence of ^p190BCR-ABL-specific T cells in the BM. Our results show that ^p190BCR-ABL-specific CTLs are capable of controlling treatment-refractory Ph⁺ ALL in vivo, and support the development of adoptive immunotherapeutic approaches with BCR-ABL CTLs in Ph⁺ ALL.