Developing allogeneic CAR-Tregs: an interview with Sangamo Therapeutics

In this interview, Jason Fontenot, SVP, Head of Cell Therapy, Sangamo Therapeutics, Inc. (WA, USA), discusses the challenges in producing therapeutic CAR-Treg cells and the opportunities presented by a new partnership with UK-based Mogrify.

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Could you introduce yourself and tell us about your role? 

I am the Head of Cell Therapy at Sangamo Therapeutics. I lead the cell therapy efforts at Sangamo including the CAR-Treg portfolio, the Sangamo collaboration with Kite/Gilead (CA, USA) to develop next generation T and NK cell therapies for oncology and other early-stage cell therapy programs. I am a T-cell immunologist by training and my previous roles included the Head of Exploratory Research at Juno Therapeutics (WA, USA), Chief Scientific Officer at Immusoft (WA, USA) and Group Leader at Biogen (MA, USA).  

What are CAR-Treg cells and how can they be utilized therapeutically? 

CAR-Tregs are regulatory T-cells (or Tregs), which are genetically re-programmed ex vivo (outside the body) to add a chimeric antigen receptor (CAR). Tregs are a type of white blood cell and are a sub-population of T-cells. They act as the key regulators of the immune system and have a targeted immunosuppressive function. They inhibit the inflammation that can be caused by other immune and non-immune cells. They have also been shown to promote tissue healing and regeneration. At Sangamo, we describe them with the metaphor of ‘peacekeepers’ because they can direct other T-cells to ceasefire to ensure the immune system does not mistakenly harm healthy organs, whilst still allowing the immune system to protect the body from foreign intruders (such as viruses and bacteria). 

CARs are artificial receptors, which give Tregs the ability to target a specific protein, called an antigen. By engineering a Treg to express a CAR, CAR-Tregs can recognize and accumulate in specific tissues where this antigen is being expressed and an immune-mediated disorder is occurring. 

Our preclinical research shows that CAR-Tregs can inhibit overactive immune cells within the body and have the potential to induce long-term immune tolerance. We are investigating CAR-Tregs in diseases where an excessive inflammatory or immune reaction is at the root of the disease. We aim to develop therapies that can induce and restore immune tolerance to address a wide range of inflammatory and autoimmune diseases. 

How do you create a CAR-Treg therapy? 

To create a CAR-Treg therapy, you need to engineer Tregs to add a CAR. These Tregs can either come from the patient, in which case we talk about autologous CAR-Treg therapy, or they can come from a different person (a healthy donor), in which case it is an allogeneic CAR-Treg therapy.  

For our most advanced CAR-Treg program in transplantation, we are currently using a lentivirus to engineer autologous Tregs with a CAR. We are also working on additional genetic engineering approaches using our proprietary zinc finger nuclease (ZFN) technology to enhance the function of Tregs and bring Treg cell therapy to as many patients as possible. 

What are some of the added challenges in producing a CAR-Treg therapy compared to a CAR-T therapy? 

CAR-T cells are made using effector T-cells, or Teffs. The quantity of Treg cells in the blood is much lower than for Teffs, since Tregs represent only 1–2% of circulating lymphocytes. Therefore, the starting material is smaller for CAR-Tregs than for CAR-Ts, which is an added production challenge. In contrast to Teffs, Tregs are also more challenging to obtain at high purity and to expand ex vivo. 

You’ve recently started a collaboration with Mogrify (Cambridge, UK). What obstacles will their cell conversion technology help you overcome? Have there been any extra challenges in creating allogeneic CAR-Treg cells? 

The collaboration with Mogrify gives us access to their cell conversion technology, which enables the transformation of any cell type into another. Our collaboration is focused on developing methods for converting induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) into Tregs. This agreement expands our options as we work to develop ‘off-the-shelf’ allogeneic CAR-Treg cell therapies. We are also exploring other avenues to create allogeneic CAR-Tregs and this new option will complement the approaches we were already working on. 

Allogeneic cell therapies can be produced from terminally differentiated cells derived from a healthy donor or, alternatively, from a renewable cell source, such as an iPSC or an ESC. Each approach has its challenges and benefits. We believe the allogeneic approach to CAR-Treg therapies has great potential and so we are exploring both of these avenues. 

The collaboration with Mogrify is focused on deriving Tregs from renewable cell sources and we believe Mogrify’s technology will help us identify a path to derive Tregs from iPSCs and ESCs.  

How is quality ensured when working with iPSCs and ESCs as a starting material? 

When using iPSCs and ESCs as a starting material it is critical to develop attributes that define the health and quality of the cells both in their base state and as they differentiate into the cell type of interest. These attributes must be defined and confirmed through detailed experimental analysis and testing.  

What are the major bottlenecks to CAR-T treatments becoming widely commercially available? 

Developing cell therapy manufacturing processes that are scalable and uniform is an important goal. Such processes will allow us to produce therapies that are accessible to all patients who can benefit from them. 

How do you foresee CAR technology evolving? 

Two important areas of innovation will be; 1) the development of ‘off-the-shelf’ allogeneic therapies and; 2) the development of more advanced engineering strategies to allow more precise programing and control of cell therapies such as gene control and synthetic biology.

Our collaboration with Mogrify is focused on the first. We have additional internal efforts focused on both of these areas. Sangamo’s genome engineering platform is a critical tool in both of these areas. 

When can we expect to see Sangamo’s CAR-Treg therapy in clinical trials? 

Our most advanced CAR-Treg candidate is TX200, which is being studied for the prevention of immune-mediated rejection following mismatched kidney transplantation. The patient’s Tregs are collected before transplant, genetically engineered with a CAR designed to bind to HLA-A2 and then injected back into the same patient after transplantation.  

We will evaluate TX200 in a clinical study to determine its safety, tolerability and mechanism of action in patients who have received a kidney transplant. The STEADFAST clinical study will help us understand how TX200 works in humans and may provide broader proof-of-concept for genetically modified cell therapy using Tregs. Our Clinical Trial Application (CTA) has been approved in the UK and we are working towards other regulatory approvals. The next step will be to initiate first clinical sites in Europe.  

Disclaimer 
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of RegMedNet or Future Science Group. 

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