Abstract
Hematopoietic stem cell–engineered invariant NK T (HSC-iNKT) cells have preclinical antitumor activity.
Major finding: Hematopoietic stem cell–engineered invariant NK T (HSC-iNKT) cells have preclinical antitumor activity.
Concept: HSC-iNKT cells directly kill CD1d+ tumor cells, activate NK cells, DCs, and CTLs, and inhibit TAMs.
Impact: These preclinical findings provide support for further clinical development of HSC-iNKT cell therapy for cancer.
Invariant natural killer T (iNKT) cells are αβT cells recognizing glycolipid antigens presented by CD1d, which are not subject to MHC restriction. iNKT cells exhibit antitumor activity via several mechanisms, including direct killing of CD1d+ tumor cells, activation of NK cells and dendritic cells (DC), stimulation of cytotoxic T cells (CTL), and inhibition of tumor-associated macrophages (TAM). It has been suggested that iNKT cells take part in tumor surveillance, and their frequencies are decreased in patients with solid tumors and hematologic malignancies. Previous clinical trials using adoptive cell transfer after ex vivo expansion or direct stimulation of iNKT cells showed some promising results but suffered from limited duration of response in a small number of patients. To overcome this obstacle, Zhu, Smith, and colleagues developed hematopoietic stem cell–engineered iNKT (HSC-iNKT) cells with potential long-lasting expansion in patients. Human HSCs engineered to express the human iNKT T-cell receptor showed long-term persistence and expansion in a human bone marrow–liver–thymus-engrafted humanized mouse model and distribution across lymphoid tissues. HSC-iNKT cells showed typical iNKT development, as well as upregulation of memory T-cell and NK-cell markers. In vitro assays confirmed the killing of tumor cells by HSC-iNKT cells using several mechanisms, including direct killing of CD1d+ cells, activation of NK cells, DCs, and CTLs, and inhibition of TAMs. CD1d-dependent antitumor efficacy of HSC-iNKT cells was shown in xenograft models of multiple myeloma and melanoma; HSC-iNKT cells efficiently infiltrated into solid tumors and homing of HSC-iNKT cells to tumors was higher than to blood, spleen, and liver. Collectively, these results support the therapeutic potential of HSC-iNKT cells for treatment of both hematologic malignancies and solid tumors.
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