Designing cells as living drugs for diseases of the immune system

Leonardo M R Ferreira, Yannick D Muller, Jeffrey A Bluestone, Qizhi Tang

Overview

This review summarizes the history, rationale, and latest developments in using regulatory T cells (Tregs), a rare subset of immunosuppressive T lymphocytes, as a treatment for disorders caused by unwanted immune responses, such as organ transplant rejection, graft-vs-host disease, and autoimmune diseases (e.g. type 1 diabetes).

Summary

With the approval of cell-based therapies, including the use of genetically modified cells (CRISPR/Cas9, chimeric antigen receptors) for cancer, it is time to expand this powerful paradigm to more diseases, namely those caused by immune rejection - organ transplant rejection, autoimmune attack - as well as other undesired immune responses, such as chronic inflammation and allergy. Here, we lay out the key characteristics an engineered Treg must have to be a safe and effective living drug: Specificity, Survival, Stability, and Suppression (4S).

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Author Comments

Leonardo Ferreira, PhD
Leonardo Ferreira, PhD
UCSF
Immune tolerance
San Francisco, California | United States
Blood has been at the forefront of cell and gene therapy due to its accessibility and decades of work on lineage tracing (there are markers for almost every cell subset imaginable, allowing their purification by FACS) and ex vivo expansion and genetic modification (retrovirus, lentivirus, AAV, and, more recently, CRISPR/Cas9 ribonucleoprotein complexes). We're at an inflection point where we're starting to use blood cell-based treatments for non-blood diseases, such as solid tumors. The next generation of this cellular approach to medicine will see the use of immune cells to a wider range of ailments, from autoimmunity and inflammation to neurological disorders. Tregs are uniquely positioned as a special subset of cells that can be purified from blood and expanded, are antigen-specific, can be redirected to any target (TCR, CAR), induce immune suppression via several mechanisms, interacting with many cell types, and promote tissue repair.Leonardo Ferreira, PhD

Resources

Tregs & Type 1 Diabetes TV talk show
https://www.youtube.com/watch?v=UWIb5ybeic8
Antigen-specific Tregs in the fast lane
https://onlinelibrary.wiley.com/doi/full/10.1111/ajt.14202
How single-cell proteomics can drive CAR Treg therapies
https://www.the-scientist.com/the-marketplace/how-single-cell-proteomics-data-can-drive-car-treg-based-therapies-an-interview-with-leonardo-ferreira-isoplexis-66601

Next-generation regulatory T cell therapy.

Authors:
Leonardo Ferreira, PhD
Leonardo Ferreira, PhD
UCSF
Immune tolerance
San Francisco, California | United States

Nat Rev Drug Discov 2019 10 20;18(10):749-769. Epub 2019 Sep 20.

Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.

Regulatory T cells (T cells) are a small subset of immune cells that are dedicated to curbing excessive immune activation and maintaining immune homeostasis. Accordingly, deficiencies in T cell development or function result in uncontrolled immune responses and tissue destruction and can lead to inflammatory disorders such as graft-versus-host disease, transplant rejection and autoimmune diseases. As T cells deploy more than a dozen molecular mechanisms to suppress immune responses, they have potential as multifaceted adaptable smart therapeutics for treating inflammatory disorders. Indeed, early-phase clinical trials of T cell therapy have shown feasibility, tolerability and potential efficacy in these disease settings. In the meantime, progress in the development of chimeric antigen receptors and in genome editing (including the application of CRISPR-Cas9) over the past two decades has facilitated the genetic optimization of primary T cell therapy for cancer. These technologies are now being used to enhance the specificity and functionality of T cells. In this Review, we describe the key advances and prospects in designing and implementing T cell-based therapy in autoimmunity and transplantation.

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Source
http://www.nature.com/articles/s41573-019-0041-4
Publisher Site
http://dx.doi.org/10.1038/s41573-019-0041-4DOI Listing
October 2019
392 Reads
41.908 Impact Factor

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