Investors back Quell’s Treg approach

Despite some impressive clinical performances, cell therapies like Car-T have yet to live up to commercial expectations. This has not stopped players hoping to harness another cell type, T regulatory cells (Tregs), from raking in the cash.

The latest is the UK's Quell Therapeutics, which raised a $156m series B round this week. But research into Tregs, which have a role in suppressing the immune system, is still at a very early stage. And, so far, efforts in this space have met with little success.

A notable example is Caladrius, whose Treg candidate fell short in type 1 diabetes several years ago. However, that group was using unmodified Tregs; the latest crop of companies is developing engineered Tregs, which they hope will improve their chances.

Tissue targeting

Quell, for one, is making several modifications; some are used in all of its Tregs, while others are indication specific.

The latter includes an HLA-A2-specific Car that has been incorporated into Quell’s lead project, the potentially once-and-done autologous therapy QEL-001. This asset is being developed to prevent rejection of HLA-A2-mismatched liver transplants, the idea being that the Car allows targeting of the therapy to the transplanted organ, thereby avoiding systemic immunosuppression.

Another Treg developer, Sangamo Therapeutics, is taking a similar approach with TX200, an autologous project that also features an HLA-A2-specific Car, but is being trialled in kidney transplantation.

Locked in

QEL-001 has another feature that TX200 does not: Quell’s so-called “phenotype lock”. This is designed to keep the cells “looking and functioning like Tregs”, explains the group’s chief executive, Iain McGill, rather than “flipping” to become effector T cells that can end up attacking the tissues they were supposed to protect.

This lock is achieved by engineering Tregs to express high levels of FoxP3; this has also been shown preclinically to increase the Tregs’ immunosuppressive potency, Mr McGill adds.

In addition, QEL-001 includes a safety switch licensed “from the world of oncology”, Mr McGill says, declining to give further details. Whether these extra modifications will translate into improved safety and/or efficacy will only be answered with clinical data.

Sangamo is already enrolling patients into its phase 1/2 Steadfast study, and expects to start dosing by mid-2022. Meanwhile, Quell’s Liberate phase 1/2 study of QEL-001 is slated to begin before the end of this year and dose the first patient in the first quarter of 2022.

Details on Liberate are so far scant, but according to Mr McGill it will enrol patients one to five years after a liver transplant with the aim of weaning them off immunosuppressive therapy. The chief exec will not say exactly what the endpoints will be, but notes that the study will look for both the absence of organ rejection and the removal of immunosuppression.

Clearly how persistent Quell's Tregs are remains a major question that will help determine whether this could indeed become a once-and-done therapy.

Instead of a control arm Quell hopes to outperform a benchmark set in previous studies that have withdrawn immunosuppressants without any concomitant therapy – for example, the A-Wish trial found that 13% of liver transplant patients could discontinue immunosuppressive drugs.

It will be a while before it becomes apparent whether Liberate has met this goal. The first data will come from an initial safety cohort, expected towards the end of 2022, with efficacy results to follow.

Type 1 diabetes and ALS

As well as getting Quell to the point of having “meaningful data” with QEL-001, the latest cash injection will allow the group to take two more projects “to the doorstep of the clinic”, Mr McGill says.

As well as transplantation, the group is focused on autoimmune and neuroinflammatory diseases, and he cites type 1 diabetes and amyotrophic lateral sclerosis as areas of interest. Notably, Coya Therapeutics is developing Tregs for ALS, with phase 2a data expected soon; COYA 101 does not feature genetically modified cells.

Meanwhile, other companies are in the clinic with IL-2 therapies designed to activate Tregs in various autoimmune diseases, including Merck & Co through its acquisition of Pandion.

Sangamo and Quell might be leading the engineered Treg space, but there are plenty of groups behind them, some of which are already commanding big bucks: in August Sonoma and Gentibio brought in private rounds of $265m and $157m respectively, while Abata Therapeutics launched in June with a $95m series A.

As for whether Quell plans an IPO any time soon, Mr McGill replies: “We’d like to be able to bring some data, at least show we can execute the trial, manufacture our cell therapy, and demonstrate that the product is safe – even if we haven’t got as far as efficacy.”