T cell receptor, or TCR, therapy is a cancer treatment that genetically reprograms immune cells, called T cells, to hunt down cancer with precision.

It’s similar to another treatment, CAR T-cell therapy, but with one key difference: CAR T-cell therapy can only spot proteins that naturally appear outside of a cancer cell.

TCR therapy, however, can also catch small protein fragments from inside the cell, which get carried to the surface and displayed like little name tags.

This ability gives TCR therapy access to a much wider range of cancer targets — a big deal for solid tumours, since most of what makes those cells cancerous is hidden inside them, not on the surface.

But there’s a bottleneck: In currently available approaches, each dose has to be custom-made from a patient’s own T cells, a process that can take weeks and cost well into the six figures.

Researchers have also explored engineering donor-derived T cells instead, which could be manufactured in advance and used off-the-shelf for many patients, but this method is largely limited because it carries the risk of graft-versus-host disease, a dangerous condition in which transplanted immune cells attack healthy tissues.

UCLA scientists have developed an approach that sidesteps both hurdles at once.

In a study published in Cell Reports Medicine, the team describes a scalable method for producing uniform batches of cancer-fighting T cells from blood stem cells found in donated cord blood, engineered to recognise a protein found in many solid tumours.

In mouse models of ovarian cancer and melanoma, a single dose of these engineered cells, called AlloESO-T cells, kept tumours in check and extended survival without triggering dangerous side effects.

“This platform brings us closer to a future where the product is already made, frozen and ready to go as soon as the patient needs,” said co-senior author Lili Yang, a professor of microbiology, immunology and molecular genetics and a member of the UCLA Broad Stem Cell Research Centre and the UCLA Health Jonsson Comprehensive Cancer Centre.

Safe by design

Rather than starting with mature, donor-derived T cells, the researchers began a step earlier — with blood stem cells found in cord blood, which naturally give rise to every type of blood and immune cell.

They then added a gene for a receptor that targets NY-ESO-1, a protein found in many solid tumours.

Fragments of NY-ESO-1 get pushed to the outer surface and displayed there, name-tag style. The researchers then grew these engineered stem cells into T cells in the lab.

Introducing that receptor this early keeps the stem cells from developing their own natural receptors as they mature.

That matters because conventional donor-derived T-cell therapies start from T cells that already carry a random assortment of natural receptors, which must be silenced with extra gene editing, since any of them could attack the patient’s healthy tissue.

“Stem cells are undifferentiated — they’re not yet mature T cells with a fixed receptor already in place,” said co-first author Yichen (John) Zhu, a graduate student in the UCLA Broad Stem Cell Research Centre Training Programme. “When we differentiate our engineered stem cells into T cells, essentially all of the resulting cells carry the same receptor and go after the same tumour target.”

Closing the escape hatch on tumour cells

Solid tumours are notorious escape artists, often shedding or hiding the very markers a therapy is built to find.

To guard against that, the AlloESO-T cells also carry natural killer cell receptors — a separate detection system — that detect stress signals many tumour cells display on their surface.

That gives the therapy a second, backup way to recognise and destroy tumour cells, independent of whether the NY-ESO-1 name tag is present at all. “Solid tumours are very diverse,” Zhu said.

“Some tumour cells lose or hide the antigen a therapy is designed to find — what we call antigen escape. When that happens, a therapy built around a single target loses its grip. Our stem cell-derived cells still have a second mechanism to kill those tumour cells.”

In lab tests against human melanoma, ovarian and prostate cancer cells, that backup let the engineered cells destroy tumour cells the main NY-ESO-1 route couldn’t catch on its own — closing an escape route that limits many single-target therapies.

Controlling tumours, extending survival

In mouse models of ovarian cancer, a single dose led to durable tumour control and extended survival, while a comparison group treated with T cells engineered from mature donor T cells kept the tumours only partially in check and developed graft-versus-host disease.

A melanoma model told the same story: The AlloESO-T cells slowed the cancer and delayed its return, while the comparison cells offered only fleeting control. The difference came down to where the cells went.

After a single infusion, the AlloESO-T cells multiplied roughly 100-fold, travelled to the tumour, expanded where they were needed and stayed active for weeks — while largely leaving healthy organs alone.

In contrast, the conventionally engineered cells spread through the liver and lungs and triggered the toxicity this new approach is designed to avoid.

Cheaper to make at massive scale

Perhaps the platform’s biggest promise is that it could put T-cell therapies within reach for many more patients.

Because the therapy starts from stem cells rather than fully formed T cells collected one patient at a time, manufacturing can run at a scale that custom-made therapies can’t match.

“From a small number of cord blood stem cells, we can generate trillions of therapeutic cells — enough for thousands of doses — within about six weeks,” said co-senior author Yanruide (Charlie) Li, a postdoctoral scholar in the Yang lab.

“At an estimated $5,000 per dose, this approach would be far more accessible than today’s therapies.”

One platform to target many solid cancers

Many solid tumours don’t carry a good target that naturally appears on their surface for a therapy to grab onto, which leaves those patients with few options.

But because this approach uses an engineered T-cell receptor — which recognises targets that originate inside the tumour cell, displayed as fragments on its surface — it could reach cancers that have been hard to treat.

“We’re not just presenting one therapy for one target. We want to share the platform itself,” Li said.

“As long as a receptor for a given cancer antigen has been validated, we can build it into this system and generate T cells specific to that target.”

This AlloESO-T platform builds on manufacturing groundwork the Yang lab has already laid for its CAR-NKT platform — a related but distinct off-the-shelf immunotherapy approach.

The team, which has already partnered with the UCLA Health Centre for Advanced Biotherapies to produce clinical-grade cells for that programme, expects to draw on that same manufacturing relationship to scale up AlloESO-T, which could help move it toward a clinical trial faster than starting from scratch.

Article: Scalable generation of hematopoietic stem cell-engineered off-the-shelf mono-specific cytotoxic T cells targeting solid tumors

Source: University of California - Los Angeles Health Sciences