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Ex vivo isolation, expansion and bioengineering of CCR7+CD95-/or CD62L+CD45RA+tumor infiltrating lymphocytes from acute myeloid leukemia patients' bone marrow
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DOI：10.1016/j.neo.2021.11.003.png)
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Abstract
En 中文
T cell based immunotherapies can be applicable to acute myeloid leukemia (AML). Therefore, the selection of optimal T cells, cell manufacturing, and therapeutic T cell engineering are essential for the development of effective adoptive T cell therapies for AML. Autologous tumor-infiltrating lymphocytes (TILs) have been in clinical trials to treat solid malignancies. Herein, we assessed whether TILs can be isolated from the bone marrow (BM) of AML patients, expanded ex vivo and utilized as a novel therapeutic strategy for AML. To this end, firstly we analyzed the immunophenotypes of a series of primary BM samples from AML patients )N = 10) by flow cytometry. We observed a variable amount of CD3+ TILs (range similar to 2.3-similar to 32.6% of mononuclear cells) among BM samples. We then developed a novel protocol that produced a three-log ex vivo expansion of TILs isolated from AML patient BM (N = 10) and peripheral blood (PB))N = 10), including from patients with a low number of CD3+ T cells, within 3, 4 weeks. Further, we identified previously described naive T cells (CCR7 +CD95-/or CD62L +CD45RA +) in AML BM and PB samples, which seemed to be required for a successful TILs ex vivo expansion. Finally, we showed that the expanded TILs could: (1) cause cytotoxicity to autologous AML blasts ex vivo (90.6% in control without T cell treatment vs. 1.89% in experimental groups with PB derived T cells and 1.77% in experimental groups with BM derived TILs, p < 0.01), (2) be genetically engineered to express CYP27B1 gene, and (3) infiltrate the BM and reside in close proximity to pre-injected autologous AML blasts of engrafted immunodeficiency mice. Altogether, these results provide a rationale for further studies of the therapeutic use of TILs in AML.
Keywords:
Acute myeloid leukemia
Tumor-Infiltrating Lymphocytes
Immunotherapy
Naive T
CCR7
CD95
CD62L
CD45RA
Bone marrow
Adoptive cell therapy
Interleukin
Programmed cell death protein 1
PD-1
CAR-T
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