T-cell therapy is a type of immunotherapy that has shown promise as an effective treatment for various cancers. But the complex, slow, unreliable, and costly development process means scaling up manufacturing is currently out of reach.
In a nutshell, T-cell therapies make a patient’s own immune cells better at fighting cancer cells. There are different subtypes of treatment, but they all generally involve collecting a sample of the patient’s immune cells, enhancing their ability to kill cancer cells in the lab, and then returning the cells to the patient.
Notch Therapeutics is a Canadian company with a potential breakthrough in the form of a cost-effective and reliable manufacturing platform called Engineered Thymic Niche (ETN). The technology can create universally compatible T-cells from donor stem cells on an industrial scale, offering an efficient way to mass manufacture T-cell therapies that are of consistent quality.
“This is a platform that could spawn many products,” said CEO David Main to the Globe and Mail. “The holy grail for cell therapy is to make it more drug-like — ready to go as soon as it’s prescribed, applicable for anybody, and being able to make it in big enough quantities that you can treat thousands of patients.”
Challenges with manufacturing cell therapies at scale
Regenerative medicine emerged from medical research, and the technology that works in clinical settings doesn’t readily translate to manufacturing facilities. With a normal drug, once you have the chemical formula right, it’s a question of getting the manufacturing process up to scale to make a million pills, thereby reducing the cost for each patient.
T-cell therapies are fundamentally different; there is no off-the-shelf, universal cell available similar to what you get with mass-manufactured pills. Cells must be sourced from a donor — either the patient themselves or a matched donor — and then be treated, quality-assured, and administered in very particular ways.
Chimeric Antigen Receptor (CAR) T-cell therapies involve taking mature T-cells and enhancing them with additional genetic material that improves their ability to seek and destroy cancer cells after reintroduction to the body via the bloodstream. Until now, CAR T-cell therapies have been significantly harder to scale because donors and recipients need to be matched, just like in the case of an organ transplant.
The matching process considers markers called human leukocyte antigens (HLAs), which are heritable and allow the immune system to tell which cells are native or alien. A close HLA match between donor and patient is essential for a transplant to work; however, across hundreds of generations, people over the world have developed all sorts of HLA genes, and some have very diverse types, making them difficult to match with donors.
One way to get around this is to use a patient’s own cells for the transplant. Although this is the most common practice today, it still means that each treatment is personalized to each patient, and the process can only begin once a patient has been identified. That can waste precious time before treatment can begin, and makes it impossible to benefit from economies of scale to bring the cost of treatment down.
The bottom line is that although these treatments can be life-saving, the costs can be upwards of $1.5 million, as with CAR T-cell therapies for conditions like leukemia.
The expense of these treatments has triggered debate, but the results are hard to argue against. In one trial, a single infusion of Kymriah (a type of CAR T-cell therapy) in 79 children with relapsed or treatment-resistant acute lymphocytic leukemia led to remission in three months for 82% of patients, and at 18 months, 70% survived. In another trial, 40% of patients in an adult population showed a “complete response” a year after treatment for diffuse, large B-cell lymphoma.
Mimicking the human thymus to mass manufacture T-cells
Notch’s system is fundamentally different because they start with universally compatible “master cells” and use a new strategy to make lots of them. The ETN platform mimics the human thymus, a gland that is a major site where T-cells naturally develop and mature in the body. Think of it as a sort of T-cell nursery. This simulated environment gives all the right cues for stem cells to grow, producing large numbers of cells that are then genetically tailored into specialized T-cells.
The resulting T-cells can be used for any T-cell-based application, including CARs, CRISPR gene therapy, and synthetic biology.
Notch can use any source of stem cells for their process. The cells are “reset” as gene-edited iPSCs (“master” stem cells) that can be then reprogrammed for an entirely different purpose from their origin. These genetically identical cells are a renewable source that do not have the HLA-matching issues found in conventional transplants, therefore bypassing the need to use donor cells or a patient’s own cells.
This opens the door for such treatments to a lot more people, especially those from diverse racial or ethnic backgrounds, who are often excluded by HLA mismatches.
“Each of those T-cells you pull out of the blood from a donor, or even a patient… each of those will be a little bit different,” said Ulrik Nielsen, Executive Chairman of Notch, to Fierce Biotech. “Maybe they have different T-cell receptors, maybe they’re at different sets of [maturation]. There are lots of genetic differences between them as well. We don’t have that when we start with [iPSCs].”
Allogene Therapeutics partnership
The ETN platform was created by two of Canada’s most renowned cell therapy researchers: Juan Carlos Zuniga-Pflucker of the Sunnybrook Research Institute and Peter Zandstra from the University of Toronto. Early backers of the company included the Centre for Commercialization of Regenerative Medicine and the Toronto Innovation Acceleration Partners (formerly known as MaRS Innovation).
In 2019, Notch announced a partnership with Allogene Therapeutics, a biopharma group creating allogeneic (donor) CAR T-cell therapies for cancer. Allogene and Notch are collaborating to research and develop allogeneic cell therapy candidates for non-Hodgkin lymphoma, leukemia, and multiple myeloma.
“Renewable-source, off-the-shelf cell therapies that may produce cells with greater consistency and at industrial scale have long been the dream for people working in this field,” said Nielsen in a press release. “We are delighted to spring into the research collaboration for [stem cell]-based AlloCAR therapies with Allogene, a leader in the allogeneic CAR T field, with the goal of expanding options for patients.”