Selection of Tumor-Specific Cytotoxic T Lymphocytes in Acute Myeloid Leukemia Patients Through the Identification of T-Cells Capable to Establish Stable Interactions With the Leukemic Cells: “Doublet Technology”

Abstract

The relevance of the immune system in cancer has long been studied. Autologous adoptive T cell therapies, based on the use of tumor infiltrating lymphocytes (TILs), have made great progress in recent years for the treatment of solid tumors, especially melanoma. However, further work is needed to isolate tumor-reactive T cells among patients diagnosed with hematologic malignancies. The dynamics of the interaction between T cells and antigen presenting cells (APC) dictate the quality of the immune responses. While stable joints between target cells and T lymphocytes lead to the induction of T cell activation and immune response, brief contacts contribute to the induction of immune-tolerance. Taking advantage of the strong interaction between target cell and activated T-cells, we show the feasibility to identify and isolate tumor-specific cytotoxic T lymphocytes (CTLs) from acute myeloid leukemia (AML) patients by flow cytometry. Using this technology, CTLs bound through T cell receptor (TCR) to tumor cells can be identified in peripheral blood and bone marrow and subsequently selected and isolated by FACS-based cell sorting. These CTLs display higher percentage of effector cells and marked cytotoxic activity against AML blasts. In conclusion, we have developed a new procedure to identify and select specific cytotoxic T cells in patients diagnosed with acute myeloid leukemia.

The immunomodulatory drugs lenalidomide and pomalidomide enhance the potency of AMG 701 in multiple myeloma preclinical models

“…This "training" or "educating" process mimics the generation of tumor-specific cytotoxic T cells and has been shown to be accelerated by BiTE molecules. 54,62,63 Our data show that T cells with memory phenotype or tumor-specific cytotoxic T cells are capable of serial target cell lysis with additional AMG 701 administration, which may result in the development of longer antitumor immunity. These mechanisms may explain the prolonged remission period and high rate of MRD negativity observed in some responders in the first-inhuman AMG 420 clinical study.…”

Single-cell map of diverse immune phenotypes in the acute myeloid leukemia microenvironment

“…5 c) (Table 1 ). Cytotoxic CD4 + effectors, with anti-tumor activity, was identified by other researchers in other tumors [ 76 – 78 ], and might lead to therapeutic benefit. And we first identified a cytotoxic CD4 + T subset under AML stress by scRNA-seq analysis.…”

RORα Regulates Cholesterol Metabolism of CD8+ T Cells for Anticancer Immunity

“…In recent years, there has been significant interest in the clinical application of cytotoxic T cells due to their central role in antitumor immunity in the tumor microenvironment [25,44,45]. In comparison to targeting cancer only, targeting both cancer and the cancer microenvironment has been demonstrated to offer benefits in cancer treatment.…”