Broad cytotoxic targeting of acute myeloid leukemia by highly polyclonal Delta One T cells

Acute myeloid leukemia (AML) remains a major clinical challenge due to frequent chemotherapy resistance and deadly relapses. We are exploring the immunotherapeutic potential of peripheral blood V  1 + T-cells, which associate with improved long-term survival of stem-cell transplant recipients, but have never been applied as adoptive cell therapy. Using our recently developed clinical-grade protocol for expansion and differentiation of “Delta One T” (DOT) cells, we found them to be highly cytotoxic against AML primary samples and cell lines, including cells selected for resistance to standard chemotherapy. Interestingly, unlike chemotherapy, DOT-cell targeting did not select for outgrowth of specific AML lineages, suggesting a broad recognition domain, which was also consistent with the striking polyclonality of the DOT-cell TCR repertoire. Moreover, whereas AML reactivity was only slightly impaired upon anti-V  1 + TCR antibody blockade, it was strongly dependent on expression of the NKp30 ligand, B7-H6. In contrast, DOT-cells did not show any reactivity against normal leukocytes, including CD33 + or CD123 + myeloid cells. Importantly, adoptive transfer of DOT-cells in vivo markedly reduced AML load in the blood and target organs of multiple human AML xenograft models; and significantly prolonged host survival, without any noticeable toxicity, thus providing the proof-of-concept for DOT-cell application in AML treatment.