Back to Search
Start Over
Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma.
- Source :
-
Cancer immunology research [Cancer Immunol Res] 2019 Jan; Vol. 7 (1), pp. 100-112. Date of Electronic Publication: 2018 Nov 05. - Publication Year :
- 2019
-
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 × 10 <superscript>6</superscript> -3 × 10 <superscript>7</superscript> 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 <superscript>+</superscript> 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.<br /> (©2018 American Association for Cancer Research.)
- Subjects :
- Adult
Aged
Cytokines immunology
Female
Humans
Ligands
Male
Middle Aged
NK Cell Lectin-Like Receptor Subfamily K genetics
NK Cell Lectin-Like Receptor Subfamily K immunology
Receptors, Chimeric Antigen immunology
T-Lymphocytes immunology
Immunotherapy, Adoptive
Leukemia, Myeloid, Acute therapy
Multiple Myeloma therapy
Myelodysplastic Syndromes therapy
Subjects
Details
- Language :
- English
- ISSN :
- 2326-6074
- Volume :
- 7
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cancer immunology research
- Publication Type :
- Academic Journal
- Accession number :
- 30396908
- Full Text :
- https://doi.org/10.1158/2326-6066.CIR-18-0307