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

Abstract

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 DOTcell 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.

γδ T cells in cancer: a small population of lymphocytes with big implications

“…Residing in tissues, Vd1 + T cells adapt to lower nutrient availability and decreased oxygen levels, which is similar to the tumor microenvironment. 113 It is thought that this is mediated through innate NK receptors in addition to TCR recognition of tumor cells. However, tumors in hypoxic environments begin to secrete soluble NKG2D ligands, rendering cd T cells incapable of killing these cells.…”

“…113 It is thought that this is mediated through innate NK receptors in addition to TCR recognition of tumor cells. 61,113 Vc9 + Vd2 + T cells have been detected in over 30 solid and haematological malignancies. This is consistent with previous reports, showing that expanded Vd1 + T cells possess broad cytotoxic potential in solid tumors, including colon cancer.…”

“…57 These cells acted against a broad range of tumor clones and did not select for resistant strains. 113 It is thought that this is mediated through innate NK receptors in addition to TCR recognition of tumor cells. Vd1 + cd T cells express a range of germ-line-encoded receptors, which recognise cellular stress (NKG2D) as well as tumor-and viral-associated antigens (NKp44 and NKp46; Figure 1).…”

The complex existence of γδ T cells following transplantation: the good, the bad and the simply confusing

“…This phenomenon is not restricted to kidney transplant patients, as CMV‐associated Vδ2‐negative γδ T cells show anti‐leukaemic effects following HSCT . However, the anti‐leukaemic effector functions of Vδ1‐positive γδ T cells were only partially dependent on TCR and strongly dependent on the expression of B7‐H6, a ligand for the NK cell receptor NKp30 …”

“…62,63 However, the anti-leukaemic effector functions of Vd1-positive cd T cells were only partially dependent on TCR and strongly dependent on the expression of B7-H6, a ligand for the NK cell receptor NKp30. 64 Vd2-positive cd T cells, in particular the Vc9Vd2 subset, have also been found to exert anti-tumor effects. Vc9Vd2 cells isolated from the blood of patients following HSCT can be expanded in vitro and efficiently lyse lymphoid and myeloid targets.…”