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Newly Identified T-Cell Receptor (TCR) on Killer T-Cells Recognizes Antigen (MR1) Present on Cells from Many Different Cancers; Discovery Offers Prospect of Universal “One Size Fits All” Therapy for Cancer

Researchers at Cardiff University in Wales have discovered a new type of killer T-cell that offers hope of a “one-size-fits-all” cancer therapy. T-cell therapies for cancer - where immune cells are removed, modified, and returned to the patient’s blood to seek and destroy cancer cells - are the latest paradigm in cancer treatments. The most widely-used therapy, known as CAR-T, is personalized to each patient, but targets only a few types of cancers and has not been successful for solid tumors, which make up the vast majority of cancers. Cardiff researchers have now discovered T-cells equipped with a new type of T-cell receptor (TCR) which recognizes and kills most human cancer types, while ignoring healthy cells. This newly discovered TCR recognizes a molecule present on the surface of a wide range of cancer cells, as well as in many of the body’s normal cells but, remarkably, is able to distinguish between healthy cells and cancerous ones, killing only the latter. The researchers said this meant it offered “exciting opportunities for pan-cancer, pan-population” immunotherapies not previously thought possible. Conventional T-cells scan the surface of other cells to find anomalies and eliminate cancerous cells - which express abnormal proteins - but ignore cells that contain only “normal” proteins. The scanning system recognizes small parts of cellular proteins that are bound to cell-surface molecules that belong to the human leukocyte antigen (HLA) system, allowing killer T-cells to see what’s occurring inside cells by scanning their surface. Proteins in the HLA system vary widely between individuals, which has previously prevented scientists from creating a single T-cell-based treatment that targets most cancers in all people. But the Cardiff study, published online on January 20, 2020 in Nature Immunology, describes a unique TCR that can recognize many types of cancer via a single HLA-like molecule called MR1. Unlike HLA proteins, MR1 does not vary in the human population - meaning it is a hugely attractive new target for immunotherapies. The article is titled "Genome-Wide CRISPR–Cas9 Screening Reveals Ubiquitous T-Cell Cancer Targeting via the Monomorphic MHC Class I-Related Protein MR1."

WHAT DID THE RESEARCHERS SHOW?

T-cells equipped with the newly discovered TCR were shown, in the lab, to kill lung, skin, blood, colon, breast, bone, prostate, ovarian, kidney and cervical cancer cells, while ignoring healthy cells.

To test the therapeutic potential of these cells in vivo, the researchers injected T-cells able to recognize MR1 into mice bearing human cancer and with a human immune system.

This showed “encouraging” cancer-clearing results, which the researchers said was comparable to the now National Health System (NHS)-approved CAR-T therapy in a similar animal model.

The Cardiff group weas further able to show that T-cells of melanoma patients modified to express this newly discovered TCR could destroy, not only the patient’s own cancer cells, but also other patients’ cancer cells in the laboratory, regardless of the patient’s HLA type.

Professor Andrew Sewell, PhD, lead author on the study and an expert in T-cells from Cardiff University’s School of Medicine, said it was “highly unusual” to find a TCR with such broad cancer specificity and this raised the prospect of “universal” cancer therapy.

“We hope this new (newly discovered) TCR may provide us with a different route to target and destroy a wide range of cancers in all individuals,” he said.
“Current TCR-based therapies can only be used in a minority of patients with a minority of cancers.”

“Cancer-targeting via MR1-restricted T-cells is an exciting new frontier - it raises the prospect of a ‘one-size-fits-all’ cancer treatment; a single type of T-cell that could be capable of destroying many different types of cancers across the population.”

“Previously nobody believed this could be possible.”

WHAT HAPPENS NEXT?

Experiments are under way to determine the precise molecular mechanism by which the newly discovered TCR distinguishes between healthy cells and cancer cells.

The researchers believe it may work by sensing changes in cellular metabolism that cause different metabolic intermediates to be presented at the cancer cell surface by MR1.

The Cardiff group hopes to trial this new approach in patients towards the end of this year, following further safety testing.
Professor Sewell said a vital aspect of this ongoing safety testing was to further ensure that killer T-cells modified with the newly discovered TCR recognize/kill cancer cells only.

“There are plenty of hurdles to overcome, however, if this testing is successful, then I would hope this new treatment could be in use in patients in a few years’ time,” he said.

Professor Oliver Ottmann, MD, Cardiff University’s Head of Hematology, whose department delivers CAR-T therapy, said: “This new type of T-cell therapy has enormous potential to overcome current limitations of CAR-T, which has been struggling to identify suitable and safe targets for more than a few cancer types.”

Professor Awen Gallimore, PhD, of the University’s Division of Infection and Immunity and Cancer Immunology and Lead for the Wales Cancer Research Centre, said: “If this transformative new finding holds up, it will lay the foundation for a ‘universal’ T-cell medicine, mitigating against the tremendous costs associated with the identification, generation, and manufacture of personalized T-cells.”

“This is truly exciting and potentially a great step forward for the accessibility of cancer immunotherapy.”

The research was funded by the Wellcome Trust, Health and Care Research Wales, and Tenovus.

Professor Kieran Walshe, Director of Health and Care Research Wales, said: “We fund research that aims to make a real difference to people’s lives. This study is a significant development in the fight against cancer and it has the potential to transform the treatment of thousands of patients.”

This discovery was covered extensively in the popular press. Please see links to representative press articles below.

[Press release] [Nature Immunology abstract] [Nature Immunology full text PDF provided by Newsweek]

[USA Today article] [Newsweek article] [BBC News article] [CBS Philly article] [The Hill article]

IMAGE

Photo shows Professor Andrew Sewell (left), PhD, with Research Fellow Garry Dolton, PhD, in the laboratory.