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

TY - JOUR

T1 - Broad Cytotoxic Targeting of Acute Myeloid Leukemia by Polyclonal Delta One T Cells

AU - Di Lorenzo, Biagio

AU - Simões, André E

AU - Caiado, Francisco

AU - Tieppo, Paola

AU - Correia, Daniel V

AU - Carvalho, Tânia

AU - da Silva, Maria Gomes

AU - Déchanet-Merville, Julie

AU - Schumacher, Ton N

AU - Prinz, Immo

AU - Norell, Haakan

AU - Ravens, Sarina

AU - Vermijlen, David

AU - Silva-Santos, Bruno

N1 - ©2019 American Association for Cancer Research.

PY - 2019/4

Y1 - 2019/4

N2 - 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.

AB - 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.

KW - Animals

KW - Cytotoxicity, Immunologic

KW - Female

KW - Humans

KW - Immunotherapy, Adoptive

KW - Leukemia, Myeloid, Acute/immunology

KW - Male

KW - Mice, Inbred NOD

KW - Mice, SCID

KW - T-Lymphocytes, Cytotoxic/immunology

U2 - 10.1158/2326-6066.CIR-18-0647

DO - 10.1158/2326-6066.CIR-18-0647

M3 - SCORING: Journal article

C2 - 30894378

VL - 7

SP - 552

EP - 558

JO - CANCER IMMUNOL RES

JF - CANCER IMMUNOL RES

SN - 2326-6066

IS - 4

ER -