Delta one T cells for immunotherapy of chronic lymphocytic leukemia: Clinical-grade expansion/differentiation and preclinical proof of concept

A.R. Almeida, D.V. Correia, A. Fernandes-Platzgummer, C.L. Da Silva, Maria Gomes da Silva, D.R. Anjos, B. Silva-Santos

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Purpose: The Vd1+ subset of gd T lymphocytes is a promising candidate for cancer immunotherapy, but the lack of suitable expansion/differentiation methods has precluded therapeutic application. We set out to develop and test (preclinically) a Vd1+ T-cell-based protocol that is good manufacturing practice compatible and devoid of feeder cells for prompt clinical translation. Experimental design: We tested multiple combinations of clinical-grade agonist antibodies and cytokines for their capacity to expand and differentiate (more than 2-3 weeks) Vd1+ T cells from the peripheral blood of healthy donors and patients with chronic lymphocytic leukemia (CLL). We characterized the phenotype and functional potential of the final cellular product, termed Delta One T (DOT) cells, in vitro and in vivo (xenograft models of CLL). Results: We describe a very robust two-step protocol for the selective expansion (up to 2,000-fold in large clinicalgrade cell culture bags) and differentiation of cytotoxic Vd1+ (DOT) cells. These expressed the natural cytotoxicity receptors, NKp30 and NKp44, which synergized with the T-cell receptor to mediate leukemia cell targeting in vitro. When transferred in vivo, DOT cells infiltrated tumors and peripheral organs, and persisted until the end of the analysis without showing signs of loss of function; indeed, DOT cells proliferated and produced abundant IFNg and TNFa, but importantly no IL17, in vivo. Critically, DOT cells were capable of inhibiting tumor growth and preventing dissemination in xenograft models of CLL. Conclusions: We provide a clinical-grade method and the preclinical proof of principle for application of a new cellular product, DOT cells, in adoptive immunotherapy of CLL. Clin Cancer Res; 22(23); 5795-804. ©2016 American Association for Cancer Research.
Original languageEnglish
Pages (from-to)5795-5804
Number of pages10
JournalClinical Cancer Research
Volume22
Issue number23
DOIs
Publication statusPublished - 2016

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