Broad Cytotoxic Targeting of Acute Myeloid Leukemia by Polyclonal Delta One T Cells
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Broad Cytotoxic Targeting of Acute Myeloid Leukemia by Polyclonal Delta One T Cells. / Di Lorenzo, Biagio; Simões, André E; Caiado, Francisco; Tieppo, Paola; Correia, Daniel V; Carvalho, Tânia; da Silva, Maria Gomes; Déchanet-Merville, Julie; Schumacher, Ton N; Prinz, Immo; Norell, Haakan; Ravens, Sarina; Vermijlen, David; Silva-Santos, Bruno.
In: CANCER IMMUNOL RES, Vol. 7, No. 4, 04.2019, p. 552-558.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -