First published in our Biotech Review of the year – issue 9.
CAR-T therapy, which essentially trains the body’s T-cells to attack cancerous tissue, has been shown to be remarkably effective, resulting in complete remission in a large number of patients who had failed to respond to more traditional cancer treatments. In the years since, the field of cell therapy has firmly stepped into the spotlight. As the number of companies moving into the field has grown, there has been rising interest in investigating different types of engineered cell therapies. A clear example is the growing interest in regulatory T-cell therapy (or Tregs). Although still a relatively new field, in the past year we have seen products begin to move into the clinic and a number of large investments in companies focussed on engineered Tregs. Here we look at what regulatory T-cell therapy is and consider the potential of the field.
What are Regulatory T-Cells?
Starting life in bone marrow, T-Cells are a form of white blood cell which play a central role in the immune response. There are a number of types of T-cell, each with a different function and role to play in controlling the body’s immune response against the variety of different pathogens we encounter on a daily basis. Perhaps the best-known function of T-cells is the ability to kill virus infected cells and even cancer cells (this “killer” function is carried out by a sub-set of T-cells known as cytotoxic T-cells). We have heard a lot about T-cells in the last couple of years as researchers have investigated the role they have to play in immunity against COVID-19.
Regulatory T-Cells, as the name might suggest, are a type of T-cell that are responsible for regulating or supressing the body’s immune response. They dial down the immune response once an infection has been brought under control and also regulate self-tolerance (i.e. making sure that the immune system does not attack a person’s own cells, or “self”). This regulatory role is vital: if the immune system is never dialled back, even after an infection has been fought off, then the body is susceptible to attack from its own immune system. This can lead to inflammation and autoimmunity (where the immune system recognises parts of a person’s body as foreign) and, in extreme cases, an overreaction by the immune system can even be fatal.
Treg Cell Therapy
It is the regulatory function of Treg cells that researchers are hoping to harness through the design and use of Treg therapies. There are a large number of potential applications for Treg cell therapies, particularly in treating people living with debilitating autoimmune diseases (such as rheumatoid arthritis, type 1 diabetes or multiple sclerosis) and to prevent complications arising from organ transplantation. The idea of harnessing the power of Treg cells to treat disease is not new and over the last decade, a number of early phase clinical trials of Treg cell therapies have already shown the feasibility, tolerability and potential efficacy of Treg cells. However, recent progress in CRISPR-based gene editing techniques and development of chimeric antigen receptors (CARs) has generated increased interest in the field, opening up the possibility of developing a next generation of more targeted engineered Treg therapies.
Autoimmune disease: Autoimmune diseases happen when a person’s immune system cannot distinguish between the person’s own cells, and foreign cells. This causes a person’s immune system to mistakenly attack the person’s own cells. There are over 80 types of recognised autoimmune conditions and the research group Connect Immune Research estimates that as many as four million people in the UK live with an autoimmune disease. This includes around 400,000 people who are living with rheumatoid arthritis (an autoimmune condition in which a person’s immune system attacks the joints). A similar number of people in the UK are living with Type 1 Diabetes, a condition in which the insulin producing beta cells in the pancreas are destroyed by a person’s own T-cells. Multiple sclerosis is another relatively common autoimmune condition in which the immune system attacks myelin (the protective sheath that covers nerve fibres) leading to nerve damage and a wide range of potentially debilitating symptoms such as fatigue and difficulty walking. The Multiple Sclerosis Society estimates that there are over 130,000 people in the UK with MS.
Companies leading the field in the development of Treg cell therapies for use in treating autoimmune conditions are testing a variety of methods but broadly the approaches taken involve genetically engineering Treg cells (either a patient’s own (autologous), or taken from donor cells (allogeneic)). The Treg cells can be engineered to selectively target different tissue types by engineering them to express a T-cell receptor (TCR) or chimeric antigen receptor (CAR) which recognises an antigen specific to a particular tissue type. These engineered Treg cells will then be administered to the patient, where they will target a particular tissue type and can locally supress the immune response at the targeted site (for example, in the pancreas in the case of type 1 diabetes).
There are a number of companies who are active in this area. For example, Boston based Gentibio is developing Treg therapies for type 1 diabetes and is aiming to begin IND-enabling (investigational new drug-enabling) studies for its product in by the end of 2021. Cambridge (Massachusetts) based Abata Therapeutics also has a Treg program targeting type 1 diabetes, alongside its lead program which targets multiple sclerosis. San Francisco based Sonoma Biotherapeutics is building a pipeline to treat a range of autoimmune conditions including rheumatoid arthritis and type 1 diabetes. Maryland based TeraImmune is also developing engineered Treg therapies for multiple sclerosis.
Solid organ transplantation: another significant market for TReg therapy is to treat complications in organ transplant patients (around 3,500 people underwent organ transplants between 2020 and 2021 in the UK). A dangerous complication of organ transplantation is the condition known as graft versus host disease. This is where a person’s immune system recognises a transplanted organ as foreign and attacks it. Unless this immune reaction is brought under control it can result in the transplanted organ being rejected. Currently, to reduce the risks of graft vs host complications, organ transplant patients are prescribed immunosuppressant drugs for the rest of their lives. Whilst these are effective, they are a systemic approach to addressing immune response complications: dampening down the body’s entire immune system and leaving the transplant patient susceptible to infections. Over the course of the COVID-19 pandemic, individuals reliant on immunosuppressant medication were categorised as critically in danger for this exact reason and even outside of a pandemic, these immunosuppressant medications can significantly affect an individual’s quality of life.
If it can be shown to be safe and effective, engineered Treg therapy therefore offers a promising potential alternative for patients reliant on immunosuppressant medications. By engineering Treg cells to target a specific part of the body (e.g. a transplanted organ), and preventing an auto-immune overreaction in the targeted location only, Treg cell therapy aims to avoid the requirement to suppress a patient’s entire immune system. While the durability of Treg therapies is not yet known, the hope is that they would remove the need for patients to rely on lifelong immunosuppressant medications.
Sangamo Therapeutics, Inc. is one of the companies leading the field in using engineered Tregs for solid organ transplantation. Sangamo received approval from the UK Medicines and Healthcare products Regulatory Agency (MHRA) for a Phase 1/2 clinical trial to evaluate its CAR-Treg therapy in 2019. The trial has recently enrolled its first patient (November 2021) and Sangamo expects to dose two more patients by mid-2022. Sangamo’s therapy is being studied for the prevention of kidney transplant rejection in patients with end-stage renal disease. Another leader in the field of developing engineered Treg therapies for solid organ transplantation is London-based Quell Therapeutics. Quell received approval from the MHRA in October 2021 for the first clinical trial of its lead CAR-Treg cell therapy (QEL-001) in liver transplant patients. Quell expects to start its clinical trial with 18 patients early in 2022.
Other areas of interest: Although research is still at an early stage, the potential uses of engineered Treg cells do not stop at autoimmune diseases and organ transplants. Researchers are also investigating other possible uses, including in various neurodegenerative diseases and also in controlling antibody reactions against Factor VIII blood clotting factor, which is used to treat patients with haemophilia A (a complication which can render the treatment with Factor VIII ineffective).
Growing Commercial Interest
Engineered Treg therapies are still in early stages of development, however, some of the most advanced therapies are now moving into the clinic and starting human trials, such as Sangamo’s Kidney transplant therapy and Quell’s liver transplant therapy mentioned above.
As development progresses, the field is seeing more and more commercial interest. Over the course of the last year, we have seen companies active in the engineered Treg cell therapy space raising increasingly large sums through investment. For example, biotherapeutics company GentiBio raised $157 million in a series A funding round in August 2021 (apparently setting a new record for the largest Series A in the Treg therapeutic space, a title formerly held by Quell Therapeutics for its series A in February 2021). In the UK, Quell Therapeutics has recently raised a further £156m ($117m) in an oversubscribed Series B funding which completed in November 2021. 2021 also saw the launch of Abata Therapeutics, raising $95m in series A funding, primarily from Third Rock Ventures.
The potential of engineered Treg therapies has also not escaped the notice of larger, more traditional pharma companies such as AstraZeneca (where Tregs form a major focus of AstraZeneca’s immune cell therapy research) and Pfizer, Johnson & Johnson Innovation, and Lilly (who are each investors in Trex Bio, a discovery stage biotech working with Tregs).
Looking to the future
As for the future of the engineered Treg market, overall, the picture is encouraging. With more companies entering the field and engineered Treg therapies beginning to enter clinical trials, these therapies may be approaching an inflection point. Whilst funding to date has largely been from specialist VC groups, larger pharmaceutical investors will undoubtedly be keeping a close eye on the space and we will be keeping an eye out for future partnerships and M&A in this space.
This growing commercial interest and news of high-profile fundraisings should attract further attention to the field, whilst also hopefully providing the pioneers with a greater ability to get their products to market. As small clusters of Treg therapy companies continue to emerge and more clinical trial results are published (hopefully confirming the safety and efficacy of these treatments), confidence amongst investors, healthcare professionals and patients will hopefully continue to increase.
While it is too early at this stage to know whether the therapies currently under development will be shown to be safe and effective, there is a lot of optimism about the potential of Treg therapies as transformative treatments in the autoimmune and transplant space. Whether they can match the success of CAR-T therapy remains to be seen but we will be watching the space with interest.