‘We want to give everyone a new thymus to reboot their immune system’

Thymmune founder says ARPA-H funding will bring ‘off-the-shelf’ thymus rejuvenation technology to human clinical trials.

Last year, the US government created a stir when it announced $37 million in ARPA-H project funding to restore function to the thymus – a relatively small but important organ that plays a crucial role in the human immune system. Located just behind our sternum, the thymus acts as a central hub for the development and maturation of T cells, which are instrumental in combating infections, diseases, and responding effectively to vaccinations.

As we age, the functionality of the thymus gradually declines, resulting in reduced production of new T cells, which leaves the body more vulnerable to infections, illnesses, and compromised health outcomes. It is thought that restoring the function of the thymus has the potential to combat age-associated immune decline and a range of immune system disorders. The ARPA-H funding aims to support the cultivation of functional thymus tissue that it is hoped can be used to “reboot” the human immune system.

Longevity.Technology: The company leading the government-funded thymus rejuvenation project is Thymmune Therapeutics, which is developing thymic cell therapies to restore immune function in aging and disease. Backed by renowned Harvard geneticist George Church, the Cambridge, MA-based startup is on a mission to use stem cells to build an “off-the-shelf” thymus that could one day be offered to everyone. To learn more, we caught up with Thymmune’s founder and CEO, Dr Stan Wang.

The thymus is at its most active throughout the early years of our lives but, by the time we’re in our 20s, its function has already depleted to a minimal level.

“From a biological perspective that seems to be okay for the first several decades of life,” says Wang. “Your body cranked up a lot of naive T cells in those first two decades, and those serve to give you protection for decades.”

US government backs thymus rejuvenation project with $37m ARPA-H funding
The thymus is a small organ located in the chest. (Photograph: Magic mine/Shutterstock)

Far from a ‘useless’ organ

The immune protection enabled by the thymus used to be enough for a lifetime – largely because human average lifespan was below 40 years for centuries.

“Now, as we hit our 50s, 60s, 70s and beyond, we’re seeing all these immune problems of aging,” says Wang. “Understandably, at that point, the T cells that your body generated early in life are starting to decline as well. They’re starting to go through immunosenescence and not be able to function as well, which means they’re not as well-equipped to respond to all the threats that you encounter in life.”

In the past, Wang says that many physicians and biologists thought that the thymus was a useless organ.

“When dissecting cadavers, they saw this big tissue early in life that essentially disappears over the course of aging and thought it must be something your body doesn’t need,” he explains. “But even recently, there’s clinical data coming out showing that if you remove the thymus from an adult who already only has a minimal level of thymus activity, you significantly increase their risk of mortality. So, it may be the case that even a minimal level of thymus activity is still somehow much safer for people than no thymus at all.”

Building an off-the-shelf thymus

All this data convinced Wang that the thymus was incredibly important in terms of the general ability of the immune system to respond effectively, and he started Thymmune to try and solve the problem of its decline.

“Biologically speaking, we think it’s relatively straightforward – we want to give everybody a new thymus gland, using an off-the-shelf cell therapy, and help everyone around the world reboot their immune system as they age,” he says. “Ultimately, we believe this would help people respond better to all forms of infections, cancers, vaccines and so on, and bolster immune health on a global scale.”

So far, so simple. But how does one go about creating an “off the shelf” thymus? Of course, the answer lies in stem cells – more specifically, the mass production of thymic cells derived from induced pluripotent stem cells (iPSCs).

“Using a process that has been informed and driven by machine learning and engineering methods to make high-quality thymic cells from iPSCs at scale,” says Wang.

The cells that Thymmune creates are suspended in a liquid formulation designed to be directly injected into the muscle of a subject (currently in humanised animal models, but hopefully soon in humans).

“What we’re seeing is that they form thymic-like cells at the site of implant and injection,” says Wang. “And this structure recapitulates the function of the human thymus at the site, producing new naive T cells that can go on and mediate downstream interactions like vaccine response, tolerance, and so on.”

From rare diseases to everyone

As with many longevity startups, while Thymmune’s long term goal is to target systemic age-related decline, the company is initially focused on a key area of unmet need – in this case, a rare genetic condition where children are born without a thymus.

“Unfortunately, this condition is usually fatal by age two or three, and the quality of life of these kids is pretty terrible because they don’t have a functional immune system,” says Wang.

The FDA recently approved a method for using donated, surgically harvested thymus tissue to restore immune function in these cases, but the approach is not without its challenges.

“The way they do it right now is they do a surgical implant into the thigh muscle,” says Wang. “It works, but it’s very invasive, both for the recipient and the donor. And, even for that rare disease, there’s a long waitlist – it can be more than a year long, and kids have died while waiting for the therapeutic.”

Thanks to the ARPA-H funding, Thymmune is now capitalized to move that program from preclinical into IND-enabling studies, and into its first human clinical trials “within the next few years.”

“We’re on the path now of advancing the preclinical data, scaling up the production of the cells, so that we can mass produce them at clinical quality for implantation,” says Wang. “We’re also preparing the necessary interfaces with regulatory agencies, and the relevant data packages to provide the agencies with reassurance that we’re doing this in the safest way possible, and that this has the potential to be effective, if not lifesaving, for this patient population.”

If Thymmune can demonstrate its technology is, first and foremost, safe to use in humans and then goes on to restore immune function in children born without a thymus, the company aims to continue its mission to ultimately give everyone a new thymus as they age.

“Of course, there’s an incredible opportunity in immunology between those two extremes,” says Wang. “There are a whole host of reasons why people end up with thymic damage or dysfunction – chemotherapy, radiation, surgery, bone marrow transplantation, and much more.”

“Our strategy will be to start from the most clinically severe and work our way down, while ensuring we have the safest product possible, until we get to a point where we can consider this as a preventative treatment for every single one of us.”