RESUMO
Regulatory T cells (Tregs) are fundamental to maintaining immune homeostasis by inhibiting immune responses to self-antigens and preventing the excessive activation of the immune system. Their functions extend beyond immune surveillance and subpopulations of tissue-resident Treg cells can also facilitate tissue repair and homeostasis. The unique ability to regulate aberrant immune responses has generated the concept of harnessing Tregs as a new cellular immunotherapy approach for reshaping undesired immune reactions in autoimmune diseases and allo-responses in transplantation to ultimately re-establish tolerance. However, a number of issues limit the broad clinical applicability of Treg adoptive immunotherapy, including the lack of antigen specificity, heterogeneity within the Treg population, poor persistence, functional Treg impairment in disease states, and in vivo plasticity that results in the loss of suppressive function. Although the early-phase clinical trials of Treg cell therapy have shown the feasibility and tolerability of the approach in several conditions, its efficacy has remained questionable. Leveraging the smart tools and platforms that have been successfully developed for primary T cell engineering in cancer, the field has now shifted towards "next-generation" adoptive Treg immunotherapy, where genetically modified Treg products with improved characteristics are being generated, as regards antigen specificity, function, persistence, and immunogenicity. Here, we review the state of the art on Treg adoptive immunotherapy and progress beyond it, while critically evaluating the hurdles and opportunities towards the materialization of Tregs as a living drug therapy for various inflammation states and the broad clinical translation of Treg therapeutics.
RESUMO
Adoptive immunotherapy (AI) with pathogen-specific T cells is a promising alternative to pharmacotherapy for the treatment of opportunistic infections after allogeneic hematopoietic cell transplantation or solid organ transplantation. However, clinical implementation of AI is limited to patients not receiving high-dose steroids, a prerequisite for optimal T-cell function, practically excluding the most susceptible to infections patients from the benefits of AI. To address this issue, we here rapidly generated, clinical doses of a steroid-resistant T-cell product, simultaneously targeting four viruses (adenovirus, cytomegalovirus, Epstein Barr virus, and BK virus) and the fungus Aspergillus fumigatus, by genetic disruption of the glucocorticoid receptor (GR) gene using CRISPR/CAS9 ribonucleoprotein delivery. The product, "Cerberus" T cells (Cb-STs), was called after the monstrous three-headed dog of Greek mythology, due to its triple potential; specificity against viruses, specificity against fungi and resistance to glucocorticoids. Following efficient on-target GR disruption and minimal off-target editing, the generated Cb-STs maintained the characteristics of pentavalent-STs, their unedited counterparts, including polyclonality, memory immunophenotype, specificity, and cytotoxicity while they presented functional resistance to dexamethasone. Cb-STs may become a powerful, one-time treatment for severely immunosuppressed patients under glucocorticoids who suffer from multiple, life-threatening infections post-transplant, and for whom therapeutic choices are limited.
