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Cancer Immunol Res. 2019 Jan;7(1):100-112. doi: 10.1158/2326-6066.CIR-18-0307. Epub 2018 Nov 5.

Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma.

Author information

1
Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.
2
Division of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
3
Division of Pediatric Hematology-Oncology Boston Children's Hospital, Boston, Massachusetts.
4
Harvard Medical School, Boston, Massachusetts.
5
Celdara Medical, LLC, Lebanon, New Hampshire.
6
Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
7
Celyad, SA, Mont-Saint-Guibert, Belgium.
8
Novartis BioMedical Institutes, Cambridge, Massachusetts.
9
Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts. sarah_nikiforow@dfci.harvard.edu.

Abstract

NKG2D ligands are widely expressed in solid and hematologic malignancies but absent or poorly expressed on healthy tissues. We conducted a phase I dose-escalation study to evaluate the safety and feasibility of a single infusion of NKG2D-chimeric antigen receptor (CAR) T cells, without lymphodepleting conditioning in subjects with acute myeloid leukemia/myelodysplastic syndrome or relapsed/refractory multiple myeloma. Autologous T cells were transfected with a γ-retroviral vector encoding a CAR fusing human NKG2D with the CD3ζ signaling domain. Four dose levels (1 × 106-3 × 107 total viable T cells) were evaluated. Twelve subjects were infused [7 acute myeloid leukemia (AML) and 5 multiple myeloma]. NKG2D-CAR products demonstrated a median 75% vector-driven NKG2D expression on CD3+ T cells. No dose-limiting toxicities, cytokine release syndrome, or CAR T cell-related neurotoxicity was observed. No significant autoimmune reactions were noted, and none of the ≥ grade 3 adverse events were attributable to NKG2D-CAR T cells. At the single injection of low cell doses used in this trial, no objective tumor responses were observed. However, hematologic parameters transiently improved in one subject with AML at the highest dose, and cases of disease stability without further therapy or on subsequent treatments were noted. At 24 hours, the cytokine RANTES increased a median of 1.9-fold among all subjects and 5.8-fold among six AML patients. Consistent with preclinical studies, NKG2D-CAR T cell-expansion and persistence were limited. Manufactured NKG2D-CAR T cells exhibited functional activity against autologous tumor cells in vitro, but modifications to enhance CAR T-cell expansion and target density may be needed to boost clinical activity.

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