Expansion of cancer germline antigen–specific cytotoxic T lymphocytes for immunotherapy

Abstract

The cancer germline antigens MAGE-A1, MAGE-A3, and NY-ESO-1 can be used to target relapsed or therapy-resistant malignant solid tumors, and previous studies have demonstrated that these antigens can be epigenetically upregulated on the surface of tumor cells following exposure to low-dose demethylating chemotherapy agents, such as decitabine. The extent to which cancer germline antigen cytotoxic T lymphocytes can be reliably expanded from healthy donors has not been well characterized, specifically in terms of whether these T cells consistently kill antigen-bearing targets or simply produce interferon-γ in the presence of the antigen. Cancer germline antigen cytotoxic T lymphocytes were generated using conventional method and high-density lymphocyte culture method. We demonstrate that there is no difference in the extent of antigen-specific killing with or without CD25 depletion when interleukin-21 is added to the cultures. Cancer germline antigen-specific killer cells could be expanded from 8/12 healthy donors using overlapping peptide mixes derived from MAGE-A1, MAGE-A3, and NY-ESO-1 and from 7/9 healthy donors using HLA-restricted epitopes. Furthermore, cytotoxic T lymphocyte derived from 4/5 patients displayed specific cytotoxicity of target cells expressing respective cancer germline antigen and HLA partially matched tumor lines. High-density lymphocyte culture prior to stimulation with cancer germline antigen peptides resulted in antigen-specific cytotoxic T lymphocyte from healthy donors and patients from whom cancer germline antigen cytotoxic T lymphocyte culture with conventional methods was not feasible. These data demonstrate that MAGE-A1-, MAGE-A3-, and NY-ESO-1-specific T cells with antigen-specific cytotoxicity can be cultured from healthy donors and patient-derived cells making adoptive immunotherapy with these cytotoxic T lymphocyte feasible.

Malignant transformation of oral leukoplakia is associated with macrophage polarization

“…Additionally, MAGE-A was identified in OLP and an association between MAGE-A expression and malignant transformation was proven [55,56,59]. MAGE-A can act as neoantigen which induces specific T-cell responses and could be used for immunotherapy [60].…”

Immune checkpoints in targeted-immunotherapy of pancreatic cancer: New hope for clinical development

“…This equal restriction of T cell activation, which is linked to CTLA-4 blockade, may describe immune related adverse events through the potentially inferior occurrence of PD-1, equivalent to a CTLA-4 blockade 52 , 65 . Comparisons between CTLA-4 and PD-1 demonstrate that they are both B7 receptor family components 66 , expressed by activated T cells 44 , 50 , expression affected by the strength and/or continuity of TCR signaling 50 , 52 , 67 , decreased T cell proliferation, glucose metabolism, cytokine manufacturing, durability and also arranging an extended T cell proliferation 17 , 39 , 50 .…”

Immuntherapie – Die neue Ära in der Onkologie

“…In the context of adoptive cell transfer, lymphocytes (mainly T cells, but also dendritic cells, NK cells and others) are isolated from the patients’ peripheral blood. Afterwards, tumor antigen specific (T) cells may be produced or expanded that are then re-infused to the patient 114 115 ( Fig. 12 ).…”

“…Anschließend können Tumorantigen-spezifische (T) Zellen hergestellt bzw. expandiert werden, die dann dem Patienten wieder verabreicht werden 114 115 ( Abb. 12 ).…”