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Cancer Immunol Res. 2019 Apr;7(4):552-558. doi: 10.1158/2326-6066.CIR-18-0647. Epub 2019 Mar 20.

Broad Cytotoxic Targeting of Acute Myeloid Leukemia by Polyclonal Delta One T Cells.

Author information

1
Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
2
Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal.
3
Lymphact - Lymphocyte Activation Technologies S.A., Coimbra, Portugal.
4
Department of Pharmacotherapy and Pharmaceutics, Institute for Medical Immunology, Université Libre de Bruxelles, Brussels, Belgium.
5
GammaDelta Therapeutics, London, United Kingdom.
6
Instituto Português de Oncologia - Francisco Gentil, Lisbon, Portugal.
7
Immunoconcept, CNRS UMR 5164, Université de Bordeaux, Bordeaux, France.
8
Netherlands Cancer Institute, Amsterdam, the Netherlands.
9
Hannover Medical School, Hannover, Germany.
10
Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal. bssantos@medicina.ulisboa.pt.

Abstract

Acute myeloid leukemia (AML) remains a clinical challenge due to frequent chemotherapy resistance and deadly relapses. We are exploring the immunotherapeutic potential of peripheral blood Vδ1+ T cells, which associate with improved long-term survival of stem-cell transplant recipients but have not yet been applied as adoptive cell therapy. Using our clinical-grade protocol for expansion and differentiation of "Delta One T" (DOT) cells, we found DOT cells to be highly cytotoxic against AML primary samples and cell lines, including cells selected for resistance to standard chemotherapy. Unlike chemotherapy, DOT-cell targeting did not select for outgrowth of specific AML lineages, suggesting a broad recognition domain, an outcome that was consistent with the polyclonality of the DOT-cell T-cell receptor (TCR) repertoire. However, AML reactivity was only slightly impaired upon Vδ1+ TCR antibody blockade, whereas it was strongly dependent on expression of the NKp30 ligand, B7-H6. In contrast, DOT cells did not show reactivity against normal leukocytes, including CD33+ or CD123+ myeloid cells. Adoptive transfer of DOT cells in vivo reduced AML load in the blood and target organs of multiple human AML xenograft models and significantly prolonged host survival without detectable toxicity, thus providing proof-of-concept for DOT-cell application in AML treatment.

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