Regulatory T cell therapy: Current and future design perspectives

Rana, Jyoti; Biswas, Moanaro

doi:10.1016/j.cellimm.2020.104193

Cited by 49 publications

(42 citation statements)

References 230 publications

(181 reference statements)

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“…The therapies involving engineered T reg cells that are expected to specifically suppress the proliferation and production of inflammatory cytokines by cytotoxic T eff cells in the pancreas and stop the destruction of pancreatic islet cells, or at least slow the progression of T1DM ( 201 ), are particularly promising. However, several considerations should be kept in mind when using these therapies, including the antigen specificity of the transferred engineered immune cells, and their interactions with the gut microbiota that may affect the therapy outcome in multiple ways ( 474 , 475 ). Advances in scientific research must always be seen in the context of clinical care, outcomes, and prognosis for children with diseases, such as T1DM, CeD, and IBD.…”

Section: Discussionmentioning

confidence: 99%

Intestinal Microbiota in Common Chronic Inflammatory Disorders Affecting Children

et al. 2021

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The incidence and prevalence rate of chronic inflammatory disorders is on the rise in the pediatric population. Recent research indicates the crucial role of interactions between the altered intestinal microbiome and the immune system in the pathogenesis of several chronic inflammatory disorders in children, such as inflammatory bowel disease (IBD) and autoimmune diseases, such as type 1 diabetes mellitus (T1DM) and celiac disease (CeD). Here, we review recent knowledge concerning the pathogenic mechanisms underlying these disorders, and summarize the facts suggesting that the initiation and progression of IBD, T1DM, and CeD can be partially attributed to disturbances in the patterns of composition and abundance of the gut microbiota. The standard available therapies for chronic inflammatory disorders in children largely aim to treat symptoms. Although constant efforts are being made to maximize the quality of life for children in the long-term, sustained improvements are still difficult to achieve. Additional challenges are the changing physiology associated with growth and development of children, a population that is particularly susceptible to medication-related adverse effects. In this review, we explore new promising therapeutic approaches aimed at modulation of either gut microbiota or the activity of the immune system to induce a long-lasting remission of chronic inflammatory disorders. Recent preclinical studies and clinical trials have evaluated new approaches, for instance the adoptive transfer of immune cells, with genetically engineered regulatory T cells expressing antigen-specific chimeric antigen receptors. These approaches have revolutionized cancer treatments and have the potential for the protection of high-risk children from developing autoimmune diseases and effective management of inflammatory disorders. The review also focuses on the findings of studies that indicate that the responses to a variety of immunotherapies can be enhanced by strategic manipulation of gut microbiota, thus emphasizing on the importance of proper interaction between the gut microbiota and immune system for sustained health benefits and improvement of the quality of life of pediatric patients.

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Section: Discussionmentioning

confidence: 99%

Intestinal Microbiota in Common Chronic Inflammatory Disorders Affecting Children

et al. 2021

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“…Such CAR Tregs have been shown to prevent xenogeneic GvHD in a humanized murine HSCT model (35). The efficacy and suppressive stability of CAR Tregs has been demonstrated in colitis and skin transplantation models (36); several mechanisms of CAR Treg-mediated suppression have been suggested.…”

Section: Engineered Treg Cells: Tcr-transduced Tregs Car Tregsmentioning

confidence: 99%

“…It is now more than a decade since the first clinical trial using adoptive Treg therapy for the treatment of GvHD after allogeneic HSCT (21), which was followed by several early-phase trials focusing on safety, feasibility and tolerability of Treg infusions. Most of these phase I or phase I/II trials used polyclonally expanded Tregs from PBMCs and have been conducted in the setting of GvHD, new-onset T1D and solid organ transplantation (36).…”

Section: Clinical Studiesmentioning

confidence: 99%

Treg Therapies Revisited: Tolerance Beyond Deletion

Pilat

Sprent

2021

Front. Immunol.

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Induction of immune tolerance is the Holy Grail in transplantation medicine and autoimmunity. Currently, patients are required to use immunosuppressive drugs for the rest of their lives, resulting in unwanted side effects and complication from global suppression of the immune response. It is well established that regulatory T cells (Tregs) are critical for the maintenance of immune tolerance towards self-antigens by several mechanisms of immune regulation, in parallel with intrathymic deletion of self-reactive T cells during ontogeny. Therefore, approaches for increasing Treg numbers or function in vivo could provide an all-purpose solution for tolerance induction. Currently, most state-of-the-art therapeutics for treating autoimmune diseases or preventing allograft rejection work either by general immunosuppression or blocking inflammatory reactions and are non-specific. Hence, these approaches cannot provide satisfactory long-term results, let alone a cure. However, in animal models the therapeutic potential of Treg expansion for inducing effective tolerance has now been demonstrated in various models of autoimmunity and allogeneic transplantation. Here, we focus on therapies for increasing the size of the Treg pool by expanding endogenous Treg numbers in vivo or by adoptive transfer of Tregs. In particular, we discuss IL-2 based approaches (low dose IL-2, IL-2 complexes) for inducing Treg expansion in vivo as well as cell-based approaches (polyclonal, antigen specific, or cell engineered) for adoptive Treg therapy. We also mention new questions arising from the first clinical studies on Treg therapy in the fields of transplantation and autoimmunity.

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“…And last but not least, CAR T-cells. CAR T-cell transplantation technology has evolved dramatically during the past 25 years ( Figure 1 ) [ 18 , 19 , 20 , 21 , 22 ]. The current version of BCMA-directed CAR T-cell therapy employs a construct with a single-chain variable fragment that recognizes the BCMA antigen, a spacer, an intracellular co-stimulatory signaling domain (often 4-1BB), and a CD3ζ intracellular domain to stimulate T-cell activation upon binding ( Figure 2 ).…”

Section: Introductionmentioning

confidence: 99%

CART-Cell Therapy: Recent Advances and New Evidence in Multiple Myeloma

Martino

Canale

Alati

et al. 2021

Cancers

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Despite the improvement in survival outcomes, multiple myeloma (MM) remains an incurable disease. Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) represents a new strategy for the treatment of relapsed/refractory MM (R/R). In this paper, we describe several recent advances in the field of anti-BCMA CAR T-cell therapy and MM. Currently, available data on anti-BCMA CART-cell therapy has demonstrated efficacy and manageable toxicity in heavily pretreated R/R MM patients. Despite this, the main issues remain to be addressed. First of all, a significant proportion of patients eventually relapse. The potential strategy to prevent relapse includes sequential or combined infusion with CAR T-cells against targets other than BCMA, CAR T-cells with novel dual-targeting vector design, and BCMA expression upregulation. Another dark side of CART therapy is safety. Cytokine release syndrome (CRS) andneurologic toxicity are well-described adverse effects. In the MM trials, most CRS events tended to be grade 1 or 2, with fewer patients experiencing grade 3 or higher. Another critical point is the extended timeline of the manufacturing process. Allo-CARs offers the potential for scalable manufacturing for on-demand treatment with shorter waiting days. Another issue is undoubtedly going to be access to this therapy. Currently, only a few academic centers can perform these procedures. Recognizing these issues, the excellent response with BCMA-targeted CAR T-cell therapy makes it a treatment strategy of great promise.

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Regulatory T cell therapy: Current and future design perspectives

Cited by 49 publications

References 230 publications

Intestinal Microbiota in Common Chronic Inflammatory Disorders Affecting Children

Intestinal Microbiota in Common Chronic Inflammatory Disorders Affecting Children

Treg Therapies Revisited: Tolerance Beyond Deletion

CART-Cell Therapy: Recent Advances and New Evidence in Multiple Myeloma

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