Role of memory T cell subsets for adoptive immunotherapy

Abstract

Adoptive transfer of primary (unmodified) or genetically engineered antigen-specific T cells has demonstrated astonishing clinical results in the treatment of infections and some malignancies. Besides the definition of optimal targets and antigen receptors, the differentiation status of transferred T cells is emerging as a crucial parameter for generating cell products with optimal efficacy and safety profiles. Long-living memory T cells subdivide into phenotypically as well as functionally different subsets (e.g. central memory, effector memory, tissue-resident memory T cells). This diversification process is crucial for effective immune protection, with probably distinct dependencies on the presence of individual subsets dependent on the disease to which the immune response is directed as well as its organ location. Adoptive T cell therapy intends to therapeutically transfer defined T cell immunity into patients. Efficacy of this approach often requires long-term maintenance of transferred cells, which depends on the presence and persistence of memory T cells. However, engraftment and survival of highly differentiated memory T cell subsets upon adoptive transfer is still difficult to achieve. Therefore, the recent observation that a distinct subset of weakly differentiated memory T cells shows all characteristics of adult tissue stem cells and can reconstitute all types of effector and memory T cell subsets, became highly relevant. We here review our current understanding of memory subset formation and T cell subset purification, and it's implications for adoptive immunotherapy.

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy

“…1-3,5-9,25,29,32,34 This perspective should promote further research and clinical translation of adoptive T cell therapy with interference of the PI3K/AKT/mTOR or Wnt-signalling pathway. 15-19,21,33 Here we show that AKT-inhibition can be used for the generation of a unique T SCM -like CD8 + T cell product for adoptive transfer.…”

Generation of Tumor Antigen-Specific iPSC-Derived Thymic Emigrants Using a 3D Thymic Culture System

“…Epigenetically, T cells silence stemness genes during the acquisition of effector gene expression (Buchholz et al, 2013; Crompton et al, 2016; Henning et al, 2018a, 2018b; Restifo and Gattinoni, 2013). Unlike effector T cells, minimally differentiated naive and memory T cells are stem cell-like and capable of robust expansion, immune reconstitution, and long-term persistence, qualities that make them of great clinical interest (Busch et al, 2016). In fact, it has been shown that such minimally differentiated T cells possess superior anti-tumor properties upon adoptive transfer in vivo and are associated with longer persistence (Gattinoni et al, 2005).…”

Complement C3-dependent uptake of targeted liposomes into human macrophages, B cells, dendritic cells, neutrophils, and MDSCs

“…8,9,19,28 Drawbacks of ex vivo techniques include high cost and lack of a memory T-cell population after inoculation into the patient. 29,30 Nanoparticle delivery systems have had some success, but often they are targeted only to macrophages and dendritic cells, and most targeted systems require costly antibodies or peptides that are difficult to store and scale up to pharmaceutical quantities. 8,9 The advantage of using OPSS-liposomes is that OPSS is a small low-cost molecule that binds endogenous complement C3 and targets all three APCs, including B cells.…”