Beyond αβ T cells: NK, iNKT, and γδT cell biology in leukemic patients and potential for off-the-shelf adoptive cell therapies for AML

Abstract

Acute myeloid leukemia (AML) remains an elusive disease to treat, let alone cure, even after highly intensive therapies such as stem cell transplants. Adoptive cell therapeutic strategies based on conventional alpha beta (αβ)T cells are an active area of research in myeloid neoplasms given their remarkable success in other hematologic malignancies, particularly B-cell-derived acute lymphoid leukemia, myeloma, and lymphomas. Several limitations have hindered clinical application of adoptive cell therapies in AML including lack of leukemia-specific antigens, on-target-off-leukemic toxicity, immunosuppressive microenvironments, and leukemic stem cell populations elusive to immune recognition and destruction. While there are promising T cell-based therapies including chimeric antigen receptor (CAR)-T designs under development, other cytotoxic lymphocyte cell subsets have unique phenotypes and capabilities that might be of additional benefit in AML treatment. Of particular interest are the natural killer (NK) and unconventional T cells known as invariant natural killer T (iNKT) and gamma delta (γδ) T cells. NK, iNKT, and γδT cells exhibit intrinsic anti-malignant properties, potential for alloreactivity, and human leukocyte-antigen (HLA)-independent function. Here we review the biology of each of these unconventional cytotoxic lymphocyte cell types and compare and contrast their strengths and limitations as the basis for adoptive cell therapies for AML.

Broadening the horizon: potential applications of CAR-T cells beyond current indications

“…have shown positive effects of other fine-tuning approaches of CAR-T cells like the targeted down-regulation of PI3K-δ ( 160 ) and the design of a non-cleavable hinge region ( 161 ). Current studies also underline the potential use of unconventional T cells like invariant natural killer T cells and γδ-T cells, since they can function without HLA-signaling and possess natural anti-tumoral activity ( 162 ).…”

Natural Killer T Cell Diversity and Immunotherapy

“…Additionally, a common trait of these unconventional T cell subpopulations is that they rapidly secrete cytokines, and some subsets co-express surface antigens related to natural killer (NK) cells, like CD161 for mucosal-associated invariant T (MAIT) cells or NKG2D for NKT and γδ T cells [32,34,35], strongly influencing an immune response after their activation. These cells are known as CD1-restricted T cells: natural killer T (NKT) cells, MHC-related 1 (MR1)-restricted T cells: MAIT cells, and γδ T cells [36].…”