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

Patrizia Comoli, Sabrina Basso, Giovanni Riva, Patrizia Barozzi, Ilaria Guido, Antonella Gurrado, Giuseppe Quartuccio, Laura Rubert, Ivana Lagreca, Daniela Vallerini, Fabio Forghieri, Monica Morselli, Paola Bresciani, Angela Cuoghi, Ambra Paolini, Elisabetta Colaci, Roberto Marasca, Antonio Cuneo, Lorenzo Iughetti, Tommaso Trenti, Franco Narni, Robin Foà, Marco Zecca, Mario Luppi and Leonardo Potenza

Key points

  • BCR-ABL-specific CTLs may be obtained by stimulation with peptides derived from BCR-ABL junctional region and alternative splicing.

  • T cell therapy with BCR-ABL-specific CTLs from healthy donors or patients mediate molecular or hematologic CR in patients with Ph+ ALL.

Abstract

While the emergence of bone marrow-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 employing 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) from Ph+ ALL patients and healthy donors, endowed with anti-leukemia activity. We treated 3 patients with Ph+ ALL with autologous or allogeneic p190BCR-ABL-specific CTLs. No post-infusion toxicity was observed, except for a grade II skin graft-versus-host disease in the patient treated for hematologic relapse. All patients obtained a molecular or hematologic complete remission after T-cell therapy, upon emergence of p190BCR-ABL-specific T cells in the bone marrow. 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.

  • Submitted July 29, 2016.
  • Accepted November 29, 2016.